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Abstract:

The present application relates to novel 3-phenylpropionic acid
derivatives which carry a branched or cyclic alkyl substituent in the
3-position, to processes for their preparation, to their use for the
treatment and/or prevention of diseases and to their use for preparing
medicaments for the treatment and/or prevention of diseases, in
particular for the treatment and/or prevention of cardiovascular
diseases.

Claims:

1. A compound of the formula (I) ##STR00219## wherein R1, R2
and R3 independently of one another represent hydrogen or methyl, L
represents a bond or represents --CH2--, R4A and R4B
independently of one another represent methyl, trifluoromethyl or ethyl
or R4A and R4B are attached to one another and together with
the carbon atom to which they are attached form a cyclopropyl or
cyclobutyl ring which may be substituted up to two times by fluorine,
R5 represents hydrogen, fluorine, methyl or methoxy, R6
represents hydrogen, fluorine, chlorine, bromine, cyano, methyl,
trifluoromethyl, ethyl, methoxy or trifluoromethoxy, R7 represents
hydrogen, fluorine, chlorine or methyl, R8A represents methyl or
ethyl, R8B represents trifluoromethyl, or R8A and R8B are
attached to one another and together with the carbon atom to which they
are attached form an optionally difluoro-substituted cyclopentyl ring of
the formula ##STR00220## R9 represents fluorine, chlorine,
bromine, cyano, (C1-C4)-alkyl, (C2-C4)-alkenyl,
cyclopropyl or cyclobutyl, where (C1-C4)-alkyl and
(C2-C4)-alkenyl may be substituted up to three times by
fluorine and cyclopropyl and cyclobutyl may be substituted up to two
times by fluorine, and R10 represents hydrogen, fluorine, chlorine,
methyl, trifluoromethyl, ethyl or methoxy, or a salt thereof.

2. The compound of claim 1, wherein: R1 represents hydrogen or
methyl, R2 represents hydrogen, R3 represents hydrogen or
methyl, L represents a bond or represents --CH2--, R4A and
R4B both represent methyl or are attached to one another and
together with the carbon atom to which they are attached form a
cyclopropyl or cyclobutyl ring which may be substituted up to two times
by fluorine, R5 represents hydrogen, fluorine, methyl or methoxy,
R6 represents fluorine, chlorine, methyl or ethyl, R7
represents hydrogen or fluorine, R8A represents methyl, R8B
represents trifluoromethyl, or R8A and R8B are attached to one
another and together with the carbon atom to which they are attached form
a difluoro-substituted cyclopentyl ring of the formula ##STR00221##
R9 represents fluorine, chlorine, (C1-C4)-alkyl,
(C2-C3)-alkenyl, cyclopropyl or cyclobutyl, where
(C1-C4)-alkyl and (C2-C3)-alkenyl may be substituted
up to three times by fluorine and cyclopropyl and cyclobutyl may be
substituted up to two times by fluorine, and R10 represents
hydrogen, fluorine, chlorine, methyl or methoxy, or a salt thereof.

3. The compound of claim 1 wherein: R1 and R2 both represent
hydrogen, R3 represents hydrogen or methyl, L represents a bond or
represents --CH2--, R4A and R4B both represent methyl or
are attached to one another and together with the carbon atom to which
they are attached form a cyclopropyl or cyclobutyl ring which may be
substituted up to two times by fluorine, R5 represents hydrogen,
fluorine or methyl, R6 represents chlorine, R7 represents
hydrogen, R8A represents methyl, R8B represents
trifluoromethyl, R9 represents fluorine, chlorine, methyl,
trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, tert-butyl,
cyclopropyl or 2,2-difluorocyclopropyl, and R10 represents hydrogen,
fluorine, methyl or methoxy, and salts, solvates and solvates of the
salts thereof.

4. A process for preparing a compound of claim 1, comprising coupling a
carboxylic acid of the formula (II) ##STR00222## in which R8A,
R8B, R9 and R10 have the meanings given in claim 1, in an
inert solvent with the aid of a condensing agent or via the intermediate
of the corresponding carbonyl chloride in the presence of a base with an
amine of the formula (III) ##STR00223## in which L, R1, R2,
R3, R4A, R4B, R5, R6 and R7 have the
meanings given in claims 1 to 3 and T1 represents
(C1-C4)-alkyl or benzyl, to give a carboxamide of the formula
(IV) ##STR00224## in which L, R1, R2, R3, R4A,
R4B, R5, R6, R7, R8A, R8B, R9,
R10 and T1 have the meanings given above, and removing T1
from the compound of formula (IV) by basic or acidic solvolysis or, when
T1 represents benzyl, also by hydrogenolysis to give a compound of
claim 1.

8. The pharmaceutical composition of claim 1 further comprising an active
compound selected from the group consisting of an organic nitrate, an NO
donor, a cGMP-PDE inhibitor, a stimulator of guanylate cyclase, an agent
having antithrombotic activity, an agent lowering blood pressure, and an
agent altering lipid metabolisms.

Description:

[0001] The present application relates to novel 3-phenylpropionic acid
derivatives which carry a branched or cyclic alkyl substituent in the
3-position, to processes for their preparation, to their use for the
treatment and/or prevention of diseases and to their use for preparing
medicaments for the treatment and/or prevention of diseases, in
particular for the treatment and/or prevention of cardiovascular
diseases.

[0002] One of the most important cellular transmission systems in
mammalian cells is cyclic guanosine monophosphate (cGMP). Together with
nitric oxide (NO), which is released from the endothelium and transmits
hormonal and mechanical signals, it forms the NO/cGMP system. Guanylate
cyclases catalyse the biosynthesis of cGMP from guanosine triphosphate
(GTP). The representatives of this family disclosed to date can be
divided both according to structural features and according to the type
of ligands into two groups: the particulate guanylate cyclases which can
be stimulated by natriuretic peptides, and the soluble guanylate cyclases
which can be stimulated by NO. The soluble guanylate cyclases consist of
two subunits and very probably contain one haem per heterodimer, which is
part of the regulatory site. The latter is of central importance for the
mechanism of activation. NO is able to bind to the iron atom of haem and
thus markedly increase the activity of the enzyme. Haem-free preparations
cannot, by contrast, be stimulated by NO. Carbon monoxide (CO) is also
able to attach to the central iron atom of haem, but the stimulation by
CO is distinctly less than that by NO.

[0003] Through the production of cGMP and the regulation, resulting
therefrom, of phosphodiesterases, ion channels and protein kinases,
guanylate cyclase plays a crucial part in various physiological
processes, in particular in the relaxation and proliferation of smooth
muscle cells, in platelet aggregation and adhesion and in neuronal signal
transmission, and in disorders caused by an impairment of the
aforementioned processes. Under pathophysiological conditions, the
NO/cGMP system may be suppressed, which may lead for example to high
blood pressure, platelet activation, increased cellular proliferation,
endothelial dysfunction, atherosclerosis, angina pectoris, heart failure,
thromboses, stroke and myocardial infarction.

[0004] A possible way of treating such disorders which is independent of
NO and aims at influencing the cGMP signaling pathway in organisms is a
promising approach because of the high efficiency and few side effects
which are to be expected.

[0005] Compounds, such as organic nitrates, whose effect is based on NO
have to date been exclusively used for the therapeutic stimulation of
soluble guanylate cyclase. NO is produced by bioconversion and activates
soluble guanylate cyclase by attaching to the central iron atom of haem.
Besides the side effects, the development of tolerance is one of the
crucial disadvantages of this mode of treatment [O. V. Evgenov et al.,
Nature Rev. Drug Disc. 5 (2006), 755].

[0006] Substances which directly stimulate soluble guanylate cyclase, i.e.
without previous release of NO, have been identified in recent years. The
indazole derivative YC-1 was the first NO-independent but haem-dependent
sGC stimulator described [Evgenov et al., ibid.]. Based on YC-1, further
substances were discovered which are more potent than YC-1 and show no
relevant inhibition of phosphodiesterases (PDE). This led to the
identification of the pyrazolopyridine derivatives BAY 41-2272, BAY
41-8543 and BAY 63-2521. Together with the recently published
structurally different substances CMF-1571 and A-350619, these compounds
form the new class of the sGC stimulators [Evgenov et al., ibid.]. A
common characteristic of this substance class is an NO-independent and
selective activation of the haem-containing sGC. In addition, the sGC
stimulators in combination with NO have a synergistic effect on sGC
activation based on a stabilization of the nitrosyl-haem complex. The
exact binding site of the sGC stimulators at the sGC is still being
debated. If the haem group is removed from the soluble guanylate cyclase,
the enzyme still has a detectable catalytic basal activity, i.e. cGMP is
still being formed. The remaining catalytic basal activity of the
haem-free enzyme cannot be stimulated by any of the stimulators mentioned
above [Evgenov et al., ibid.].

[0007] In addition, NO- and haem-independent sGC activators, with BAY
58-2667 as prototype of this class, have been identified. Common
characteristics of these substances are that in combination with NO they
only have an additive effect on enzyme activation, and that the
activation of the oxidized or haem-free enzyme is markedly higher than
that of the haem-containing enzyme [Evgenov et al., ibid.; J. P. Stasch
et al., Br. J. Pharmacol. 136 (2002), 773; J. P. Stasch et al., J. Clin.
Invest. 116 (2006), 2552]. Spectroscopic studies show that BAY 58-2667
displaces the oxidized haem group which, as a result of the weakening of
the iron-histidine bond, is attached only weakly to the sGC. It has also
been shown that the characteristic sGC haem binding motif Tyr-x-Ser-x-Arg
is absolutely essential both for the interaction of the negatively
charged propionic acids of the haem group and for the action of BAY
58-2667. Against this background, it is assumed that the binding site of
BAY 58-2667 at the sGC is identical to the binding site of the haem group
[J. P. Stasch et al., J. Clin. Invest. 116 (2006), 2552].

[0008] The compounds described in the present invention are now likewise
capable of activating the haem-free form of soluble guanylate cyclase.
This is also confirmed by the fact that these novel activators firstly
have no synergistic action with NO at the haem-containing enzyme and that
secondly their action cannot be blocked by the haem-dependent inhibitor
of soluble guanylate cyclase, 1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one
(ODQ), but is even potentiated by this inhibitor [cf. O. V. Evgenov et
al., Nature Rev. Drug Disc. 5 (2006), 755; J. P. Stasch et al., J. Clin.
Invest. 116 (2006), 2552].

[0009] It was thus an object of the present invention to provide novel
compounds which act as activators of soluble guanylate cyclase in the
manner described above and can be used as such in particular for the
treatment and prevention of cardiovascular disorders.

[0030] Compounds according to the invention are the compounds of the
formula (I) and their salts, solvates and solvates of the salts, the
compounds included in the formula (I) of the formulae mentioned in the
following and their salts, solvates and solvates of the salts, and the
compounds included in the formula (I) and mentioned in the following as
embodiment examples and their salts, solvates and solvates of the salts,
where the compounds included in the formula (I) and mentioned in the
following are not already salts, solvates and solvates of the salts.

[0031] Preferred salts in the context of the present invention are
physiologically acceptable salts of the compounds according to the
invention. Salts which are not themselves suitable for pharmaceutical
uses but can be used, for example, for isolation, purification or storage
of the compounds according to the invention are also included.

[0032] Physiologically acceptable salts of the compounds according to the
invention include in particular salts of conventional bases, such as, by
way of example and preferably, alkali metal salts (e.g. sodium and
potassium salts), alkaline earth metal salts (e.g. calcium and magnesium
salts) and ammonium salts derived from ammonia or organic amines having 1
to 16 C atoms, such as, by way of example and preferably, ethylamine,
diethylamine, triethylamine, N,N-diisopropylethylamine, monoethanolamine,
diethanolamine, triethanolamine, dimethylaminoethanol,
diethylaminoethanol, procaine, dicyclohexylamine, dibenzylamine,
N-methylpiperidine, N-methylmorpholine, arginine, lysine and
1,2-ethylenediamine.

[0033] Solvates in the context of the invention are designated as those
forms of the compounds according to the invention which form a complex in
the solid or liquid state by coordination with solvent molecules.
Hydrates are a specific form of solvates, in which the coordination takes
place with water. Hydrates are preferred solvates in the context of the
present invention.

[0034] Depending on their structure, the compounds according to the
invention may exist in different stereoisomeric forms, i.e. in the form
of configurational isomers or if appropriate also as conformational
isomers (enantiomers and/or diastereomers, including those in the case of
atropisomers). The present invention therefore encompasses the
enantiomers or diastereomers and the respective mixtures thereof. The
stereoisomerically uniform constituents can be isolated from such
mixtures of enantiomers and/or diastereomers in a known manner;
chromatography processes are preferably used for this, in particular HPLC
chromatography on an achiral or chiral phase.

[0035] Where the compounds according to the invention can occur in
tautomeric forms, the present invention encompasses all the tautomeric
forms.

[0036] The present invention also encompasses all suitable isotopic
variants of the compounds according to the invention. An isotopic variant
of a compound according to the invention is understood here to mean a
compound in which at least one atom within the compound according to the
invention has been exchanged for another atom of the same atomic number,
but with a different atomic mass than the atomic mass which usually or
predominantly occurs in nature. Examples of isotopes which can be
incorporated into a compound according to the invention are those of
hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine,
chlorine, bromine and iodine, such as 2H (deuterium), 3H
(tritium), 13C, 14C, 15N, 17O, 18O, 32P,
33P, 33S, 34S, 35S, 36S, 18F, 36Cl,
82Br, 123I, 124I, 129I and 131I. Particular
isotopic variants of a compound according to the invention, especially
those in which one or more radioactive isotopes have been incorporated,
may be beneficial, for example, for the examination of the mechanism of
action or of the active compound distribution in the body; due to
comparatively easy preparability and detectability, especially compounds
labelled with 3H or 14C isotopes are suitable for this purpose.
In addition, the incorporation of isotopes, for example of deuterium, can
lead to particular therapeutic benefits as a consequence of greater
metabolic stability of the compound, for example an extension of the
half-life in the body or a reduction in the active dose required; such
modifications of the compounds according to the invention may therefore
in some cases also constitute a preferred embodiment of the present
invention. Isotopic variants of the compounds according to the invention
can be prepared by generally used processes known to those skilled in the
art, for example by the methods described below and the methods described
in the working examples, by using corresponding isotopic modifications of
the particular reagents and/or starting compounds therein.

[0037] The present invention moreover also includes prodrugs of the
compounds according to the invention. The term "prodrugs" here designates
compounds which themselves can be biologically active or inactive, but
are converted (for example metabolically or hydrolytically) into
compounds according to the invention during their dwell time in the body.

[0038] As prodrugs, the present invention comprises in particular
hydrolysable ester derivatives of the carboxylic acids of the formula (I)
according to the invention. These are to be understood as meaning esters
which can be hydrolysed to the free carboxylic acids, as the compounds
that are mainly active biologically, in physiological media, under the
conditions of the biological tests described later and in particular in
vivo by enzymatic or chemical routes. (C1-C4)-alkyl esters, in
which the alkyl group can be straight-chain or branched, are preferred as
such esters. Particular preference is given to methyl, ethyl or
tert-butyl esters.

[0039] In the context of the present invention, the substituents have the
following meaning, unless specified otherwise:

[0040] (C1-C4)-Alkyl in the context of the invention represents
a straight-chain or branched alkyl radical having 1 to 4 carbon atoms.
The following may be mentioned by way of example and by way of
preference: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl and tert-butyl.

[0041] (C2-C4)-Alkenyl and (C2-C3)-alkenyl in the
context of the invention represent a straight-chain or branched alkenyl
radical having a double bond and 2 to 4 and 2 or 3 carbon atoms,
respectively. A straight-chain or branched alkenyl radical having 2 or 3
carbon atoms is preferred. The following may be mentioned by way of
example and by way of preference: vinyl, allyl, n-prop-1-en-1-yl,
iso-propenyl, n-but-1-en-1-yl, n-but-2-en-1-yl, n-but-3-en-1-yl,
2-methylprop-1-en-1-yl and 2-methyl-prop-2-en-1-yl.

[0042] In the context of the present invention, all radicals which occur
more than once are defined independently of one another. If radicals in
the compounds according to the invention are substituted, the radicals
may be mono- or polysubstituted, unless specified otherwise. Substitution
by one, two or three identical or different substituents is preferred.
Particular preference is given to substitution by one or two identical or
different substituents.

[0043] In the context of the present invention, preference is given to
compounds of the formula (I) in which

[0044] R1 represents hydrogen
or methyl,

[0045] R2 represents hydrogen,

[0046] R3 represents
hydrogen or methyl,

[0047] L represents a bond or represents
--CH2--,

[0048] R4A and R4B both represent methyl or are
attached to one another and together with the carbon atom to which they
are attached form a cyclopropyl or cyclobutyl ring which may be
substituted up to two times by fluorine,

[0049] R5 represents
hydrogen, fluorine, methyl or methoxy,

[0050] R6 represents
fluorine, chlorine, methyl or ethyl,

[0051] R7 represents hydrogen
or fluorine,

[0052] R8A represents methyl,

[0053] R8B
represents trifluoromethyl,

[0054] or

[0055] R8A and R8B are
attached to one another and together with the carbon atom to which they
are attached form a difluoro-substituted cyclopentyl ring of the formula

[0057] (C1-C4)-alkyl and
(C2-C3)-alkenyl may be substituted up to three times by
fluorine

[0058] and

[0059] cyclopropyl and cyclobutyl may be substituted
up to two times by fluorine, and R10 represents hydrogen, fluorine,
chlorine, methyl or methoxy, and salts, solvates and solvates of the
salts thereof.

[0060] A particular embodiment of the present invention comprises
compounds of the formula (I) in which

R1 and R2 both represent hydrogen, and salts, solvates and
solvates of the salts thereof.

[0061] A further particular embodiment of the present invention comprises
compounds of the formula (I) in which

R3 represents hydrogen or methyl and L represents a bond, and salts,
solvates and solvates of the salts thereof.

[0062] A further particular embodiment of the present invention comprises
compounds of the formula (I) in which

R3 represents hydrogen and L represents --CH2--, and salts,
solvates and solvates of the salts thereof.

[0063] A further particular embodiment of the present invention comprises
compounds of the formula (I) in which

R4A and R4B both represent methyl and R5 represents
hydrogen, and salts, solvates and solvates of the salts thereof.

[0064] A further particular embodiment of the present invention comprises
compounds of the formula (I) in which

[0065] R4A and R4B are
attached to one another and together with the carbon to which they are
attached form a cyclopropyl or cyclobutyl ring which may be substituted
up to two times by fluorine,

[0066] and

[0067] R5 represents
hydrogen, fluorine or methyl,

[0068] and salts, solvates and solvates of
the salts thereof.

[0069] A further particular embodiment of the present invention comprises
compounds of the formula (I) in which

R6 represents chlorine and R7 represents hydrogen, and salts,
solvates and solvates of the salts thereof.

[0070] A further particular embodiment of the present invention comprises
compounds of the formula (I) in which

R8A represents methyl and R8B represents trifluoromethyl, and
salts, solvates and solvates of the salts thereof.

[0071] A further particular embodiment of the present invention comprises
compounds of the formula (I) in which

[0072] R8A and R8B are
attached to one another and together with the carbon atom to which they
are attached form a difluoro-substituted cyclopentyl ring of the formula

##STR00004##

[0072] and salts, solvates and solvates of the salts thereof.

[0073] A further particular embodiment of the present invention comprises
compounds of the formula (I) in which

[0074] R9 represents fluorine,
chlorine, (C1-C4)-alkyl or cyclopropyl, where
(C1-C4)-alkyl may be substituted up to three times by fluorine
and cyclopropyl may be substituted up to two times by fluorine,

[0075]
and salts, solvates and solvates of the salts thereof.

[0076] A further particular embodiment of the present invention comprises
compounds of the formula (I) in which

[0077] Particular preference in the context of the present invention is
given to compounds of the formula (I) in which

[0078] R1 and R2
both represent hydrogen,

[0079] R3 represents hydrogen or methyl,

[0080] L represents a bond or represents --CH2--,

[0081] R4A
and R4B both represent methyl or are attached to one another and
together with the carbon atom to which they are attached form a
cyclopropyl or cyclobutyl ring which may be substituted up to two times
by fluorine,

[0091] Of particular importance in the context of the present invention
are compounds of the formula (I-A)

##STR00005##

in which the carbon atom marked * of the phenylacetamide grouping has the
S-configuration shown and the radicals R3, R4A, R4B,
R5, R6, R8A, R8B, R9 and R10 and L each
have the meanings given above, and salts, solvates and solvates of the
salts thereof.

[0092] The definitions of radicals indicated specifically in the
respective combinations or preferred combinations of radicals are
replaced as desired irrespective of the particular combinations indicated
for the radicals also by definitions of radicals of other combinations.
Combinations of two or more of the abovementioned preferred ranges are
very particularly preferred.

[0093] The invention furthermore provides a process for preparing the
compounds of the formula (I) according to the invention, characterized in
that a carboxylic acid of the formula (II)

##STR00006##

in which R8A, R8B, R9 and R10 have the meanings given
above, is coupled in an inert solvent with the aid of a condensing agent
or via the intermediate of the corresponding carbonyl chloride in the
presence of a base with an amine of the formula (III)

##STR00007##

in which L, R1, R2, R3, R4A, R4B, R5,
R6 and R7 have the meanings given above and T1 represents
(C1-C4)-alkyl or benzyl, to give a carboxamide of the formula
(IV)

##STR00008##

in which L, R1, R2, R3, R4A, R4B, R5,
R6, R7, R8A, R8B, R9, R10 and T1 have
the meanings given above, and the ester radical T1 is then removed
by basic or acidic solvolysis or, in the case that T1 represents
benzyl, also by hydrogenolysis to give the carboxylic acid of the formula
(I) and the compounds of the formula (I) are optionally separated by
methods known to the person skilled in the art into their enantiomers
and/or diastereomers and/or reacted with the appropriate (i) solvents
and/or (ii) bases to give their solvates, salts and/or solvates of the
salts.

[0094] Inert solvents for the process step (II)+(III)→(IV) [amide
coupling] are, for example, ethers such as diethyl ether, tert-butyl
methyl ether, tetrahydrofuran, 1,4-dioxane, glycol dimethyl ether or
di-ethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene,
xylene, hexane, cyclohexane or mineral oil fractions, halogenated
hydrocarbons such as dichloromethane, trichloromethane, carbon
tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or
other solvents such as acetone, acetonitrile, ethyl acetate, pyridine,
dimethyl sulphoxide (DMSO), N,N-dimethylformamide (DMF),
N,N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP). It is
also possible to use mixtures of the solvents mentioned. Preference is
given to using dichloromethane, tetrahydrofuran, dimethylformamide or
mixtures of these solvents.

[0095] Suitable condensing agents for these coupling reactions are, for
example, carbodiimides such as N,N'-diethyl-, N,N'-dipropyl-,
N,N'-diisopropyl-, N,N'-dicyclohexylcarbodiimide (DCC) or
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC),
phosgene derivatives such as N,N'-carbonyldiimidazole (CDI) or isobutyl
chloroformate, 1,2-oxazolium compounds such as
2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl
5-methylisoxazolium perchlorate, acyl-amino compounds such as
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, α-chloroenamines
such as 1-chloro-2-methyl-1-dimethylamino-1-propene, phosphorus compounds
such as propane-phosphonic anhydride, diethyl cyanophosphonate,
bis(2-oxo-3-oxazolidinyl)phosphoryl chloride,
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate
or benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate
(PyBOP), or uronium compounds such as
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU),
2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate
(TPTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetra-methyluronium
hexafluorophosphate (HATU) or
O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetra-methyluronium
tetrafluoroborate (TCTU), if appropriate in combination with further
auxiliaries such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide
(HOSu), and as bases alkali metal carbonates, for example sodium
carbonate or potassium carbonate, or tertiary amine bases such as
triethylamine, N-methylmorpholine, N-methylpiperidine,
N,N-diisopropylethylamine, pyridine or 4-N,N-dimethylaminopyridine.
Preference is given to using
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) in combination with pyridine or
N,N-diisopropylethylamine, or
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) in
combination with 1-hydroxybenzotriazole (HOBt) and triethylamine, or
1-chloro-2-methyl-1-dimethylamino-1-propene together with pyridine.

[0096] The reaction (II)+(III)→(IV) is generally carried out in a
temperature range of from 0° C. to +60° C., preferably at
from +10° C. to +40° C.

[0097] When a carbonyl chloride corresponding to the compound (II) is
used, the coupling with the amine component (III) is carried out in the
presence of a customary organic auxiliary base such as triethylamine,
N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine,
pyridine, 4-N,N-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) or 1,5-diazabicyclo-[4.3.0]non-5-ene (DBN). Preference is given to
using triethylamine or N,N-diisopropylethylamine.

[0098] The reaction of the amine (III) with the carbonyl chloride is
generally carried out in a temperature range of from -20° C. to
+60° C., preferably in the range from -10° C. to
+30° C.

[0099] For their part, the preparation of the carbonyl chlorides is
carried out in a customary manner by treating the carboxylic acid (II)
with thionyl chloride or oxalyl chloride.

[0100] The removal of the ester group T1 in process step
(IV)→(I) is carried out by customary methods by treating the ester
in inert solvents with acids or bases, where in the latter variant the
salt initially formed is converted by treatment with acid into the free
carboxylic acid. In the case of the tert-butyl esters, the ester cleavage
is preferably carried out using acids. Benzyl esters are preferably
cleaved by hydrogenolysis (hydrogenation) in the presence of a suitable
catalyst such as, for example, palladium on activated carbon.

[0101] Suitable inert solvents for these reactions are water or organic
solvents customary for ester cleavage. These preferably include alcohols
such as methanol, ethanol, n-propanol, isopropanol, n-butanol or
tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, dioxane
or glycol dimethyl ether, or other solvents such as acetone,
dichloromethane, dimethylformamide or dime-thyl sulphoxide. It is also
possible to use mixtures of the solvents mentioned above. In the case of
a basic ester hydrolysis, preference is given to using mixtures of water
with dioxane, tetrahydrofuran, methanol and/or ethanol. In the case of
the reaction with trifluoroacetic acid, preference is given to using
dichloromethane and in the case of the reaction with hydrogen chloride,
preference is given to using tetrahydrofuran, diethyl ether, dioxane or
water.

[0102] Suitable bases are the customary inorganic bases. These include in
particular alkali or alkaline earth metal hydroxides such as, for
example, lithium hydroxide, sodium hydroxide, potassium hydroxide or
barium hydroxide, or alkali or alkaline earth metal carbonates such as
sodium carbonate, potassium carbonate or calcium carbonate. Preference is
given to lithium hydroxide, sodium hydroxide or potassium hydroxide.

[0103] Suitable acids for the ester cleavage are, in general, sulphuric
acid, hydrogen chloride/hydrochloric acid, hydrogen bromide/hydrobromic
acid, phosphoric acid, acetic acid, trifluoroacetic acid,
toluenesulphonic acid, methanesulphonic acid or trifluoromethanesulphonic
acid or mixtures thereof, if appropriate with addition of water.
Preference is given to hydrogen chloride or trifluoroacetic acid in the
case of the tert-butyl esters and hydrochloric acid in the case of the
methyl esters.

[0104] The ester cleavage is generally carried out in a temperature range
of from -20° C. to +100° C., preferably at from 0°
C. to +60° C.

[0105] The intermediates of the formula (II) can be prepared, for example,
by

[A] initially deprotonating a carboxylic acid of the formula (V)

##STR00009##

[0106] in which R8A and R8B have the meanings
given above

[0107] and

[0108] T2 represents (C1-C4)-alkyl
or benzyl,

[0109] in an inert solvent with the aid of a base and then
arylating in the presence of a suitable

[0110] palladium catalyst with a phenyl bromide of the formula (VI)

##STR00010##

[0111] in which R9 and R10 have the meanings
give above,

[0112] to give a compound of the formula (VII)

[0112] ##STR00011##

[0113] in which R8A, R8B, R9,
R10 and T2 have the meanings given above, or [B] alkylating a
phenylacetic ester of the formula (VIII)

[0113] ##STR00012##

[0114] in which R9 and R10 have the
meanings given above

[0115] and

[0116] T2 represents
(C1-C4)-alkyl or benzyl,

[0117] in an inert solvent in the
presence of a base with a compound of the formula (IX)

[0117] ##STR00013##

[0118] in which R8A and R8B have the
meanings given above

[0119] and

[0120] X1 represents a suitable
leaving group such as, for example, bromine or iodine,

[0121] to give the
compound of the formula (VII)

[0121] ##STR00014##

[0122] in which R8A, R8B, R9,
R10 and T2 have the meanings given above, and then in each case
removing the ester radical T2 by basic or acidic solvolysis or, in
the case that T2 represents benzyl, also by hydrogenolysis, giving
the carboxylic acid (II).

[0123] The arylation reaction in process step (V)+(VI)→(VII) is
preferably carried out in toluene or toluene/tetrahydrofuran mixtures in
a temperature range of from +20° C. to +100° C. Here, the
base used for deprotonating the ester (V) is preferably lithium
bis(trimethylsilyl)amide. Suitable palladium catalysts are, for example,
palladium(II) acetate or tris(dibenzylideneacetone)di-palladium, in each
case in combination with an electron-rich, sterically demanding phosphine
ligand such as 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl or
2-di-tert-butyl-phosphino-2'-(N,N-dimethylamino)biphenyl [cf., for
example, W. A. Moradi, S. L. Buchwald, J. Am. Chem. Soc. 123, 7996-8002
(2001)].

[0124] Inert solvents for the alkylation reaction (VIII)+(IX)→(VII)
are, for example, ethers such as diethyl ether, methyl tert-butyl ether,
dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol
dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane,
cyclohexane or mineral oil fractions, or dipolar aprotic solvents such as
N,N-dimethylformamide (DMF), dimethyl sulphoxide (DMSO),
N,N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP). It is
also possible to use mixtures of the solvents mentioned. Preference is
given to using tetrahydro-furan, dimethylformamide or mixtures thereof.

[0125] Suitable bases for the process step (VIII)+(IX)→(VII) are
customary strong inorganic or organic bases. These include in particular
alkali metal alkoxides such as sodium methoxide or potassium methoxide,
sodium ethoxide or potassium ethoxide or sodium tert-butoxide or
potassium tert-butoxide, alkali metal hydrides such as sodium hydride or
potassium hydride, or amides such as lithium bis(trimethylsilyl)amide,
sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)-amide or
lithium diisopropylamide. Preference is given to using potassium
tert-butoxide, sodium hydride or lithium diisopropylamide.

[0126] The reaction (VIII)+(IX)→(VII) is generally carried out in a
temperature range of from -80° C. to +40° C., preferably at
from -20° C. to +20° C.

[0127] The removal of the ester group T2 in process step
(VII)→(II) is carried out in an analogous manner as described
above for the ester radical T1.

[0128] Alternatively, intermediates of the formula (II-A)

##STR00015##

in which R9 and R10 have the meanings given above, can also be
prepared by initially converting the phenylacetic ester of the formula
(VIII)

##STR00016##

in which R9, R10 and T2 have the meanings given above, by
base-induced addition to 2-cyclopenten-1-one into a compound of the
formula (X)

##STR00017##

in which R9, R10 and T2 have the meanings given above,
then fluorinating this compound with
1,1'-[(trifluoro-λ4-sulphanyl)imino]bis(2-methoxyethane) under
boron trifluoride catalysis to give a compound of the formula (VII-A)

##STR00018##

in which R9, R10 and T2 have the meanings given above, and
subsequently removing the ester group T2 again giving the carboxylic
acid (II-A).

[0129] In process step (VIII)→(X), for deprotonating the ester
(VIII), preference is given to using an amide base such as lithium
diisopropylamide or lithium bis(trimethylsilyl)amide. For the
deoxy-fluorination in the transformation (X)→(VII-A), instead of
the 1,1'-[(trifluoro-λ4-sulphanyl)-imino]bis(2-methoxyethane)
("Desoxofluor") mentioned above, it is also possible, if appropriate, to
employ other known fluorinating agents, such as diethylaminosulphur
trifluoride (DAST) or morpholinosulphur trifluoride (morpho-DAST) [for
the reaction sequence (VIII)→(X)→(VII-A), cf., for example,
T. Mase et al., J. Org. Chem. 66 (20), 6775-6786 (2001)].

[0130] Depending on their substitution pattern, the intermediates of the
formula (III) can be prepared, for example, by either

[C-1] reacting a phosphonoacetic ester of the formula (XI)

##STR00019##

[0131] in which R1 and T1 have the meanings
given above

[0132] and

[0133] R11 represents
(C1-C4)-alkyl,

[0134] in an inert solvent in a base-induced
olefination reaction with a 3-nitrobenzoyl compound of the formula (XII)

[0134] ##STR00020##

[0135] in which L, R4A, R4B, R5,
R6 and R7 have the meanings given above,

[0136] to give a
compound of the formula (XIII)

[0136] ##STR00021##

[0137] in which L, R1, R4A, R4B,
R5, R6, R7 and T1 have the meanings given above,

[0138] and then hydrogenating this compound in the presence of a suitable
palladium or platinum catalyst to give a 3-(3-aminophenyl)propionic ester
of the formula (III-A)

[0138] ##STR00022##

[0139] in which L, R1, R4A, R4B,
R5, R6, R7 and T1 have the meanings given above, or
[C-2] reacting a phosphonoacetic ester of the formula (XI)

[0139] ##STR00023##

[0140] in which R1 and T1 have the
meanings given above

[0141] and

[0142] R1 represents
(C1-C4)-alkyl

[0143] in an inert solvent in a base-induced
olefination reaction with a protected 3-aminobenzoyl compound of the
formula (XIV)

[0143] ##STR00024##

[0144] in which L, R4A, R4B, R5,
R6 and R7 have the meanings given above

[0148] in which L, PG, R1, R4A,
R4B, R5, R6, R7 and T1 have the meanings given
above,

[0149] then either (i) reducing this compound with magnesium in
methanol to give a compound of the formula (XVI)

[0149] ##STR00026##

[0150] in which L, PG, R1, R4A,
R4B, R5, R6, R7 and T1 have the meanings given
above,

[0151] and subsequently removing the amino protective groups PG
according to customary methods by hydrogenolysis or oxidatively giving
the 3-(3-aminophenyl)propionic ester of the formula (III-A)

[0151] ##STR00027##

[0152] in which L, R1, R4A, R4B,
R5, R6, R7 and T1 have the meanings given above,

[0153] or (ii) converting the compound of the formula (XV) in a one-step
process by hydrogenation in the presence of a suitable palladium or
platinum catalyst into the 3-(3-aminophenyl)propionic ester of the
formula (III-A), or [D] coupling an acrylic ester derivative of the
formula (XVII)

[0153] ##STR00028##

[0154] in which L, R1, R4A, R4B,
R5 and T1 have the meanings given above,

[0155] in an inert
solvent under palladium catalysis with a 3-amino- or 3-nitrophenyl
bromide of the formula (XVIII)

[0155] ##STR00029##

[0156] in which R6 and R7 have the
meanings given above

[0157] and

[0158] R12 represents amino or
nitro,

[0159] to give a compound of the formula (XIX)

[0159] ##STR00030##

[0160] in which L, R1, R4A, R4B,
R5, R6, R7, R12 and T1 have the meanings given
above,

[0161] and then reducing this compound with hydrogen in the
presence of a suitable palladium or platinum catalyst or, in the case
that R12 represents amino, alternatively with magnesium in methanol
to give the 3-(3-aminophenyl)propionic ester of the formula (III-A)

[0161] ##STR00031##

[0162] in which L, R1, R4A, R4B,
R5, R6, R7 and T1 have the meanings given above, or
[E-1] converting a phenyl iodide of the formula (XX)

[0162] ##STR00032##

[0163] in which R6 and R7 have the
meanings given above,

[0164] in an inert solvent with isopropylmagnesium
chloride in the presence of lithium chloride into the corresponding
phenylmagnesium compound, then coupling this compound in situ under
copper(I) catalysis with an alkylidenemalonic ester of the formula (XXI)

[0164] ##STR00033##

[0165] in which L, R3, R4A, R4B
and R5 have the meanings given above

[0166] and

[0167] T3
represents methyl or ethyl,

[0168] to give a compound of the formula
(XXII)

[0168] ##STR00034##

[0169] in which L, R3, R4A, R4B,
R5, R6, R7 and T3 have the meanings given above,

[0170] then removing one of the two ester groupings by heating with
lithium chloride in a DMSO/water mixture, then converting the resulting
3-phenylpropionic ester of the formula (XXIII)

[0170] ##STR00035##

[0171] in which L, R3, R4A, R4B,
R5, R6, R7 and T3 have the meanings given above,

[0172] by reaction with nitronium tetrafluoroborate into the
3-nitrophenyl derivative of the formula (XXIV)

[0172] ##STR00036##

[0173] in which L, R3, R4A, R4B,
R5, R6, R7 and T3 have the meanings given above,

[0174] and finally hydrogenating in the presence of a suitable palladium
or platinum catalyst to give a 3-(3-aminophenyl)propionic ester of the
formula (III-B)

[0174] ##STR00037##

[0175] in which L, R3, R4A, R4B,
R5, R6, R7 and T3 have the meanings given above, or
[E-2] converting a protected 3-aminophenyl iodide of the formula (XXV)

[0179] in an inert
solvent with isopropylmagnesium chloride in the presence of lithium
chloride into the corresponding phenyl magnesium compound, then coupling
this compound in situ under copper(I) catalysis with an alkylidenemalonic
ester of the formula (XXI)

[0179] ##STR00039##

[0180] in which L, R3, R4A, R4B
and R5 have the meanings given above

[0181] and

[0182] T3
represents methyl or ethyl,

[0183] to give a compound of the formula
(XXVI)

[0183] ##STR00040##

[0184] in which L, PG, R3, R4A,
R4B, R5, R6, R7 and T3 have the meanings given
above, then deprotecting this compound by hydrogenolysis or by treatment
with a suitable oxidizing agent such as, for example,
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to give a compound of the
formula (XXVII)

[0184] ##STR00041##

[0185] in which L, R3, R4A, R4B,
R5, R6, R7 and T3 have the meanings given above,

[0186] and then removing one of the two ester groupings by heating with
lithium chloride in a DMSO/water mixture, to give the
3-(3-aminophenyl)propionic ester of the formula (III-B)

[0186] ##STR00042##

[0187] in which L, R3, R4A, R4B,
R5, R6, R7 and T3 have the meanings given above, or
[F] alkylating a carboxylic ester of the formula (XXVIII)

[0187] ##STR00043##

[0188] in which R1, R2 and T1 have
the meanings given above,

[0189] in an inert solvent after
α-deprotonation with a 3-bromobenzyl compound of the formula (XXIX)

[0189] ##STR00044##

[0190] in which L, R4A, R4B, R5,
R6 and R7 have the meanings given above

[0194] in which L, R1, R2, R4A,
R4B, R5, R6, R7 and T1 have the meanings given
above,

[0195] then reacting with benzylamine in the presence of a base
and a palladium catalyst to give a compound of the formula (XXXI)

[0195] ##STR00046##

[0196] in which L, R1, R2, R4A,
R4B, R5, R6, R7 and T1 have the meanings given
above,

[0197] and then removing the N-benzyl group by hydrogenolysis, to
give a 3-(3-aminophenyl)propionic ester of the formula (III-C)

[0197] ##STR00047##

[0198] in which L, R1, R2, R4A,
R4B, R5, R6, R7 and T1 have the meanings given
above.

[0199] Suitable for deprotonating the phosphono ester (XI) in the
olefination reactions (XI)+(XII)→(XIII) and (XI)+(XIV)→(XV)
are in particular non-nucleophilic strong bases such as, for example,
sodium hydride or potassium hydride, lithium bis(trimethylsilyl)amide,
sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide or
lithium diisopropylamide; preference is given to using sodium hydride.

[0200] The hydrogenation in the process steps (XIII)→(III-A),
(XV)→(III-A), (XIX)→(III-A) and (XXIV)→(III-B) is
generally carried out under a stationary hydrogen atmosphere at
atmospheric or elevated pressure. The preferred catalyst used is
palladium or platinum on activated carbon (as support material). The
removal of the amino protective group(s) in the transformations
(XVI)→(III-A), (XXVI)→(XXVII) and (XXXI)→(III-C) is
usually carried out by hydrogenolysis according to the same procedure; if
PG in (XVI) or (XXVI) represents p-methoxybenzyl, this may alternatively
also be carried out oxidatively, for example with the aid of
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or ammonium cerium(IV)
nitrate.

[0201] Preferred for use as palladium catalyst for the reaction
(XVII)+(XVIII)→(XIX) [Heck reaction] is palladium(II) acetate or
tris(dibenzylideneacetone)dipalladium(0), in each case in combination
with a phosphine ligand such as, for example, tri-tert-butylphosphine,
triphenylphosphine or tri-2-tolylphosphine.

[0202] The conversion of the phenyl iodide (XX) into the corresponding
phenylmagnesium compound and its copper(I)-mediated 1,4-addition to the
alkylidenemalonate (XXI) to give the product of the formula (XXII) are
carried out by a general method known from the literature [see, for
example, P. Knochel et al., Tetrahedron 56, 2727-2731 (2000), and the
literature cited therein]; this also applies to the analogous reaction
(XXV)+(XXI)→(XXVI).

[0203] Particularly suitable for the α-deprotonation of the
carboxylic ester (XXVIII) in the alkylation reaction
(XXVIII)+(XXIX)→(XXX) are non-nucleophilic strong bases such as,
for example, sodium tert-butoxide or potassium tert-butoxide, sodium
hydride or potassium hydride, lithium diisopropylamide or lithium
bis(trimethylsilyl)amide; sodium bis(trimethylsilyl)amide or potassium
bis(trimethylsilyl)amide; preference is given to using lithium
diisopropylamide.

[0204] Preferred inert solvents for this reaction are ethers such as
diethyl ether, diisopropyl ether, methyl tert-butyl ether,
tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl
ether. The reaction is usually carried out in a temperature range of from
-80° C. to +25° C.

[0206] The reactions described above can be carried out at atmospheric
pressure, at elevated pressure or at reduced pressure (for example in the
range of from 0.5 to 5 bar); in general in each case carried out at
atmospheric pressure.

[0207] Separation of the compounds according to the invention into the
corresponding enantiomers and/or diastereomers can take place where
appropriate, depending on expediency, even at the stage of the compounds
(II), (III), (IV), (VII), (XVI), (XXII), (XXIII), (XXIV), (XXVI),
(XXVII), (XXX) or (XXXI), which are then reacted further in separated
form in accordance with the above-described process sequences. Such
separation of the isomers can be carried out by conventional methods
known to a person skilled in the art. In the context of the present
invention, preference is given to using chromatographic methods on
achiral or chiral separation phases; in the case of carboxylic acids and
as intermediates or end products, separation may alternatively also be
via diastereomeric salts.

[0208] The compounds of the formulae (V), (VI), (VIII), (IX), (XI), (XII),
(XIV), (XVII), (XVIII), (XX), (XXI), (XXV), (XXVIII) and (XXIX) are
either commercially available or described as such in the literature, or
they can be prepared in a manner obvious to the person skilled in the art
analogously to the methods published in the literature. Numerous detailed
procedures and literature references for preparing the starting materials
can also be found in the Experimental Part in the section on the
preparation of the starting materials and intermediates.

[0209] The preparation of the compounds according to the invention can be
illustrated in an exemplary manner by the reaction schemes below:

##STR00048##

##STR00049##

##STR00050##

##STR00051##

##STR00052##

##STR00053##

##STR00054##

##STR00055##

[0210] The compounds according to the invention have valuable
pharmacological properties and can be used for the prevention and
treatment of disorders in humans and animals.

[0211] The compounds according to the invention are potent activators of
soluble guanylate cyclase. They lead to vasorelaxation, inhibition of
platelet aggregation and lowering of blood pressure and increase of
coronary blood flow. These effects are mediated via direct
haem-independent activation of soluble guanylate cyclase and an increase
of intracellular cGMP.

[0212] In addition, the compounds according to the invention have
advantageous pharmacokinetic properties, in particular with respect to
their bioavailability and/or duration of action after intravenous or oral
administration.

[0213] The compounds according to the invention are particularly suitable
for the treatment and/or prevention of cardiovascular, pulmonary,
thromboembolic and fibrotic disorders.

[0216] In addition, the compounds according to the invention can also be
employed for the treatment and/or prevention of arteriosclerosis, a
disturbed lipid metabolism, hypolipoproteinaemias, dilipideamias,
hypertriglyceridaemias, hyperlipidaemias, combined hyperlipidaemias,
hyper-cholesterolaemias, abetalipoproteinaemias, sitosterolaemia,
xanthomatosis, Tangier disease, adiposity, obesity and metabolic
syndrome.

[0217] Furthermore, the compounds according to the invention can be used
for the treatment and/or prevention of primary and secondary Raynaud's
phenomenon, of microcirculation impairments, claudication, tinnitus,
peripheral and autonomic neuropathies, diabetic microangiopathies,
diabetic retinopathy, diabetic ulcers on the extremities, gangrene, CREST
syndrome, erythematosis, onychomycosis and rheumatic disorders.

[0218] In addition, the compounds according to the invention can be used
for preventing ischaemia- and/or reperfusion-related damage to organs or
tissues and also as additives for perfusion and preservation solutions of
organs, organ parts, tissues or tissue parts of human or animal origin,
in particular for surgical interventions or in the field of
transplantation medicine.

[0219] The compounds according to the invention are furthermore suitable
for the treatment and/or prevention of kidney disorders, in particular of
renal insufficiency and renal failure. In the context of the present
invention, the terms renal insufficiency and renal failure comprise both
acute and chronic manifestations thereof, as well as underlying or
related kidney diseases such as renal hypoperfusion, intradialytic
hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis,
acute glomerulonephritis, glomerulosclerosis, tubulointerstitial
diseases, nephropathic diseases such as primary and congenital kidney
disease, nephritis, immunological kidney diseases such as kidney graft
rejection and immunocomplex-induced kidney diseases, nephropathy induced
by toxic substances, nephropathy induced by contrast agents, diabetic and
non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis,
hypertensive nephrosclerosis and nephrotic syndrome, which can be
characterized diagnostically for example by abnormally reduced creatinine
and/or water excretion, abnormally raised blood concentrations of urea,
nitrogen, potassium and/or creatinine, altered activity of renal enzymes
such as, for example, glutamyl synthetase, altered urine osmolarity or
urine volume, increased microalbuminurea, macroalbuminurea, lesions on
glomerulae and arterioles, tubular dilatation, hyperphosphataemia and/or
need for dialysis. The present invention also comprises the use of the
compounds according to the invention for the treatment and/or prevention
of sequelae of renal insufficiency, such as, for example hypertension,
pulmonary oedema, heart failure, uraemia, anaemia, electrolyte
disturbances (for example hypercalaemia, hyponatraemia) and disturbances
in bone and carbohydrate metabolism.

[0222] The compounds described in the present invention also represent
active compounds for controlling central nervous system diseases
characterized by disturbances of the NO/cGMP system. They are suitable in
particular for improving perception, concentration, learning or memory
after cognitive impairments like those occurring in particular in
association with situations/diseases/syndromes such as mild cognitive
impairment, age-associated learning and memory impairments,
age-associated memory loss, vascular dementia, craniocerebral trauma,
stroke, dementia occurring after strokes (post-stroke dementia),
post-traumatic craniocerebral trauma, general concentration impairments,
concentration impairments in children with learning and memory problems,
Alzheimer's disease, Lewy body dementia, dementia with degeneration of
the frontal lobes including Pick's syndrome, Parkinson's disease,
progressive nuclear palsy, dementia with corticobasal degeneration,
amyolateral sclerosis (ALS), Huntington's disease, demyelinisation,
multiple sclerosis, thalamic degeneration, Creutzfeld-Jakob dementia, HIV
dementia, schizophrenia with dementia or Korsakoff's psychosis. They are
also suitable for the treatment and/or prevention of central nervous
system disorders such as states of anxiety, tension and depression,
CNS-related sexual dysfunctions and sleep disturbances, and for
controlling pathological disturbances of the intake of food, stimulants
and addictive substances.

[0223] The compounds according to the invention are furthermore also
suitable for controlling cerebral blood flow and thus represent effective
agents for controlling migraine. They are also suitable for the
prophylaxis and control of the sequelae of cerebral infarctions
(Apoplexia cerebri) such as stroke, cerebral ischaemias and
craniocerebral trauma. The compounds according to the invention can
likewise be employed for controlling states of pain.

[0224] In addition, the compounds according to the invention have
antiinflammatory action and can therefore be used as antiinflammatory
agents for the treatment and/or prevention of sepsis (SIRS), multiple
organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic
inflammation of the bowel (IBS, Crohn's disease, ulcerative colitis),
pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin
diseases and inflammatory eye diseases.

[0225] The compounds according to the invention are furthermore suitable
for the treatment and/or prevention of fibrotic disorders of the internal
organs such as, for example, the lung, the heart, the kidney, the bone
marrow and in particular the liver, and also dermatological fibroses and
fibrotic eye disorders. In the context of the present invention, the term
fibrotic disorders includes in particular the following disorders:
hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis,
endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial
renal fibrosis, fibrotic damage resulting from diabetes, bone marrow
fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids,
hypertrophic scarring, naevi, diabetic retinopathy, proliferative
vitreoretinopathy and disorders of the connective tissue (for example
sarcoidosis). The compounds according to the invention can also be used
to promote wound healing, for controlling postoperative scarring, for
example as a result of glaucoma operations, and cosmetically for aging
and keratinized skin.

[0226] By virtue of their activity profile, the compounds according to the
invention are particularly suitable for the treatment and/or prevention
of cardiovascular disorders such as heart failure, angina pectoris,
hypertension and pulmonary hypertension, and also of thromboembolic
disorders and ischaemias, vascular disorders, disturbances of
microcirculation, renal insufficiency, fibrotic disorders and
arteriosclerosis.

[0227] The present invention further relates to the use of the compounds
according to the invention for the treatment and/or prevention of
disorders, especially of the aforementioned disorders.

[0228] The present invention further relates to the use of the compounds
according to the invention for producing a medicament for the treatment
and/or prevention of disorders, especially of the aforementioned
disorders.

[0229] The present invention further relates to the use of the compounds
according to the invention in a method for the treatment and/or
prevention of disorders, especially of the aforementioned disorders.

[0230] The present invention further relates to a method for the treatment
and/or prevention of disorders, especially of the aforementioned
disorders, by using an effective amount of at least one of the compounds
according to the invention.

[0231] The compounds according to the invention can be employed alone or,
if required, in combination with other active compounds. The present
invention further provides medicaments comprising at least one of the
compounds according to the invention and one or more further active
compounds, especially for the treatment and/or prevention of the
aforementioned disorders. Preferred examples of suitable active compound
combinations include:

[0238] Agents having antithrombotic activity preferably mean compounds
from the group of platelet aggregation inhibitors, of anticoagulants or
of profibrinolytic substances.

[0239] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a platelet
aggregation inhibitor such as, by way of example and preferably, aspirin,
clopidogrel, ticlopidin or dipyridamol.

[0240] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a thrombin
inhibitor such as, by way of example and preferably, ximelagatran,
melagatran, dabigatran, bivalirudin or clexane.

[0241] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a GPIIb/IIIa
antagonist such as, by way of example and preferably, tirofiban or
abciximab.

[0242] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a factor Xa
inhibitor such as, by way of example and preferably, rivaroxaban,
apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b,
PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC
906, JTV 803, SSR-126512 or SSR-128428.

[0243] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with heparin or a low
molecular weight (LMW) heparin derivative.

[0244] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a vitamin K
antagonist such as, by way of example and preferably, coumarin.

[0246] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a calcium
antagonist such as, by way of example and preferably, nifedipine,
amlodipine, verapamil or diltiazem.

[0247] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with an alpha-1 receptor
blocker such as, by way of example and preferably, prazosin.

[0248] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a beta receptor
blocker such as, by way of example and preferably, propranolol, atenolol,
timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol,
metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol,
betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol,
carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

[0249] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with an angiotensin AII
antagonist such as, by way of example and preferably, losartan,
candesartan, valsartan, telmisartan or embusartan.

[0250] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with an ACE inhibitor
such as, by way of example and preferably, enalapril, captopril,
lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or
trandopril.

[0251] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with an endothelin
antagonist such as, by way of example and preferably, bosentan,
darusentan, ambrisentan or sitaxsentan.

[0252] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a renin inhibitor
such as, for example and preferably, aliskiren, SPP-600 or SPP-800.

[0253] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a mineralocorticoid
receptor antagonist such as, for example and preferably, spironolactone
or eplerenone.

[0254] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a diuretic, such
as, for example and preferably, furosemide, bumetanide, torsemide,
bendroflumethiazide, chlorothiazide, hydrochlorothiazide,
hydro-flumethiazide, methyclothiazide, polythiazide, trichlormethiazide,
chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide,
dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol,
amiloride or triamterene.

[0256] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a CETP inhibitor
such as, by way of example and preferably, torcetrapib (CP-529 414),
JJT-705 or CETP vaccine (Avant).

[0257] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a thyroid receptor
agonist such as, by way of example and preferably, D-thyroxin,
3,5,3'-triiodothyronin (T3), CGS 23425 or axitirome (CGS 26214).

[0258] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with an HMG-CoA
reductase inhibitor from the class of the statins such as, by way of
example and preferably, lovastatin, simvastatin, pravastatin,
fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

[0259] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a squalene
synthesis inhibitor such as, by way of example and preferably, BMS-188494
or TAK-475.

[0260] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with an ACAT inhibitor
such as, by way of example and preferably, avasimibe, melinamide,
pactimibe, eflucimibe or SMP-797.

[0261] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with an MTP inhibitor
such as, by way of example and preferably, implitapide, BMS-201038,
R-103757 or JTT-130.

[0262] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a PPAR-gamma
agonist such as, by way of example and preferably, pioglitazone or
rosiglitazone.

[0263] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a PPAR-delta
agonist such as, for example and preferably, GW 501516 or BAY 68-5042.

[0264] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a cholesterol
absorption inhibitor such as, by way of example and preferably,
ezetimibe, tiqueside or pamaqueside.

[0265] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a lipase inhibitor
such as, by way of example and preferably, orlistat.

[0266] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a polymeric bile
acid adsorbent such as, by way of example and preferably, cholestyramine,
colestipol, colesolvam, CholestaGel or colestimide.

[0267] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a bile acid
reabsorption inhibitor such as, by way of example and preferably, ASBT
(=IBAT) inhibitors, for example AZD-7806, S-8921, AK-105, BARI-1741,
SC-435 or SC-635.

[0268] In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a lipoprotein(a)
antagonist such as, by way of example and preferably, gemcabene calcium
(CI-1027) or nicotinic acid.

[0269] The present invention further provides medicaments which comprise
at least one compound according to the invention, typically together with
one or more inert, nontoxic, pharmaceutically suitable auxiliaries, and
the use thereof for the aforementioned purposes.

[0270] The compounds according to the invention may act systemically
and/or locally. For this purpose, they can be administered in a suitable
manner, for example by the oral, parenteral, pulmonal, nasal, sublingual,
lingual, buccal, rectal, dermal, transdermal, conjunctival, otic route,
or as an implant or stent.

[0271] The compounds according to the invention can be administered in
administration forms suitable for these administration routes.

[0272] Suitable administration forms for oral administration are those
which work according to the prior art, which release the compounds
according to the invention rapidly and/or in a modified manner and which
contain the compounds according to the invention in crystalline and/or
amorphized and/or dissolved form, for example tablets (uncoated or coated
tablets, for example with gastric juice-resistant or retarded-dissolution
or insoluble coatings which control the release of the compound according
to the invention), tablets or films/wafers which disintegrate rapidly in
the oral cavity, films/lyophilizates or capsules (for example hard or
soft gelatin capsules), sugar-coated tablets, granules, pellets, powders,
emulsions, suspensions, aerosols or solutions.

[0273] Parenteral administration can bypass an absorption step (e.g.
intravenously, intraarterially, intracardially, intraspinally or
intralumbally) or include an absorption (e.g. intramuscularly,
subcutaneously, intracutaneously, percutaneously or intraperitoneally).
Administration forms suitable for parenteral administration include
preparations for injection and infusion in the form of solutions,
suspensions, emulsions, lyophilizates or sterile powders.

[0277] In general, it has been found to be advantageous in the case of
parenteral administration to administer amounts of about 0.001 to 1
mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to achieve
effective results. In the case of oral administration, the dosage is
about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and most
preferably 0.1 to 10 mg/kg of body weight.

[0278] It may nevertheless be necessary where appropriate to deviate from
the stated amounts, specifically as a function of the body weight, route
of administration, individual response to the active compound, nature of
the preparation and time or interval over which administration takes
place. For instance, in some cases, less than the aforementioned minimum
amount may be sufficient, while in other cases the upper limit mentioned
must be exceeded. In the case of administration of relatively large
amounts, it may be advisable to divide these into several individual
doses over the course of the day.

[0279] The working examples which follow illustrate the invention. The
invention is not limited to the examples.

[0280] The percentages in the tests and examples which follow are, unless
indicated otherwise, percentages by weight; parts are parts by weight.
Solvent ratios, dilution ratios and concentration data for liquid/liquid
solutions are based in each case on volume.

[0354] At -70° C. and under argon, 6.8 ml (96 mmol) of DMSO in 10
ml of dichloromethane were added dropwise to a mixture of 24 ml (48 mmol)
of a 2 M solution of oxalyl chloride in dichloromethane and a further 100
ml of dichloromethane, and the mixture was stirred for 15 minutes. 5.2 ml
(48 mmol) of 2-methoxy-2-methylpropan-1-ol [H. Garcia et al., Chem. Eur.
J. 16 (28), 8530-8536 (2010)], dissolved in 15 ml of dichloromethane,
were then added dropwise, and the mixture was stirred at -70° C.
for another 15 min. 22.1 ml (158 mmol) of triethylamine were added
slowly, and the reaction mixture was then stirred for another 15 min and
subsequently slowly warmed to room temperature. 22 g (58 mmol) of
tert-butyl (triphenyl-λ5-phosphanylidene)acetate were then
added, and the reaction mixture was stirred at room temperature
overnight. The reaction solution was then slowly added to 100 ml of
ice-water, and the phases obtained were separated. The organic phase was
washed twice with in each case 100 ml of water, dried over magnesium
sulphate and concentrated under reduced pressure on a rotary evaporator
(water bath temperature 40° C., pressure not below 150 mbar). The
residue obtained was taken up in about 100 ml of diethyl ether and
allowed to stand in a fridge at +3° C. for 2 days. The
precipitated triphenylphosphine oxide was filtered off, and the filtrate
was concentrated under reduced pressure. The residue obtained was
purified by chromatography on silica gel (mobile phase cyclohexane/ethyl
acetate 100:1→50:1). This gave 7.06 g (73% of theory) of the title
compound as a colourless liquid.

[0355] GC-MS (method 6): Rt=3.32 min, m/z=218 (M+NH4).sup.+.

[0356] The two compounds below were obtained analogously to synthesis
Example 1A:

[0357] Under argon, a mixture of 3.22 g (15.6 mmol) of
5-bromo-2-chloroaniline, 3.0 g (23.4 mmol) of
methyl-(2E)-4-methylpent-2-enoate, 143 mg (0.16 mmol) of
tris(dibenzylideneacetone)-dipalladium, 63 mg (0.31 mmol) of
tri-tert-butylphosphine and 3.64 ml (17.2 mmol) of
N,N-dicyclohexylmethylamine in 30 ml of dioxane were heated to
120° C. and stirred at this temperature for three days. Both after
the first and after the second day of the reaction, the same amount of
palladium catalyst and phosphine ligand was added to the reaction
mixture. The reaction mixture was then filtered through Celite, and the
filtrate was concentrated under reduced pressure. The residue was
separated into its components by chromatography on silica gel (mobile
phase cyclohexane/ethyl acetate 50:1). This gave 1.52 g of methyl
(2E/Z)-3-(3-amino-4-chloro-phenyl)-4-methylpent-2-enoate (38% of theory)
and 906 mg of methyl 3-(3-amino-4-chlorophenyl)-4-methylpent-3-enoate
(22% of theory).

[0365] A solution of 11.1 ml (116.1 mmol) of oxalyl chloride in 50 ml of
abs. dichloromethane was cooled to -78° C., and a solution of 16.5
ml (232.2 mmol) of DMSO in 50 ml of abs. dichloromethane was added
dropwise, keeping the temperature below -50° C. After 5 min, a
solution of 10.0 g (116.1 mmol) of cyclobutanemethanol in 20 ml of abs.
dichloromethane was added dropwise. After a further 15 min of stirring at
-78° C., 80.9 ml (580.5 mmol) of triethylamine were added. After 5
min, cooling was removed and the mixture was slowly warmed to RT, and the
reaction mixture was then added to water. The mixture was saturated with
sodium chloride and the separated organic phase was washed twice with
saturated sodium chloride solution, three times with 1 N hydrochloric
acid and three times with pH buffer solution, dried over sodium sulphate
and concentrated under reduced pressure (500 mbar). This gave 6.28 g of
cyclobutanecarbaldehyde as a crude product which was directly reacted
further.

Step 2:

[0366] 6.4 ml (27.3 mmol) of tert-butyl (diethoxyphosphoryl)acetate were
added dropwise to a suspension, cooled to 0° C., of 1.05 g (60% in
mineral oil, 26.2 mmol) of sodium hydride in a mixture of 22 ml of THF
and 22 ml of DMF. After 30 min, the mixture was cooled to -10° C.,
and 2.0 g (crude, about 23.8 mmol) of cyclobutanecarbaldehyde were added
in several portions. The reaction mixture was stirred at 0° C. for
5 h and then slowly warmed to RT overnight, subsequently added to water
and extracted three times with ethyl acetate. The organic phases were
combined and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (mobile phase cyclohexane/ethyl
acetate 50:1). This gave 1.21 g of the target product (about 28% of
theory).

[0369] 0.78 ml (5.60 mmol) of triethylamine was added to a mixture of
385.2 mg (1.87 mmol) of 5-bromo-2-chloroaniline and 510 mg (2.80 mmol) of
tert-butyl (2E)-3-cyclobutylacrylate in 2.8 ml of DMF. The mixture was
evacuated three times and in each case vented with argon. After the
addition of 41.9 mg (0.187 mmol) of palladium(II) acetate and 113.6 mg
(0.373 mmol) of tri-2-tolylphosphine, the reaction mixture was evacuated
two more times and in each case vented with argon and then stirred at
150° C. for 3 h. A further 193 mg of 5-bromo-2-chloroaniline were
then added, and the reaction mixture was stirred at 150° C. for
another 1 h. After cooling, the reaction mixture was filtered through
Celite and the filter residue was washed twice with DMF. The combined
filtrate was concentrated under high vacuum, and by chromatography on
silica gel (mobile phase cyclohexane/ethyl acetate 60:1) the two isomeric
target products were isolated from the residue. This gave 203 mg of
tert-butyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylacrylate (35.4% of
theory) and 137 mg of tert-butyl
3-(3-amino-4-chlorophenyl)-3-cyclobutylidene-propanoate (23.8% of
theory).

[0378] At RT, a solution of 6.77 g (26.7 mmol) of methyl
2E/Z)-3-(3-amino-4-chlorophenyl)-4-methylpent-2-enoate in 130 ml of
methanol was added to 2.2 g (90.7 mmol) of magnesium turnings and a few
grains of iodine. After about 30 min, the internal temperature increased
to about 60° C. After the reaction solution had cooled to room
temperature, stirring at room temperature was continued for another 2 h.
50 ml of saturated aqueous ammonium chloride solution were then added
slowly to the dark reaction mixture, and the mixture was extracted
repeatedly with diethyl ether. The combined organic phases were washed
with saturated sodium bicarbonate solution and saturated sodium chloride
solution, dried over magnesium sulphate and concentrated under reduced
pressure. The residue obtained was purified by chromatography on silica
gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 2.95 g (40%
of theory) of the title compound as an oil.

[0395] Under argon, 12.62 g (316.16 mmol, 60% in mineral oil) of sodium
hydride were suspended in 250 ml of abs. DMF and cooled to 0° C.
32 g (126.3 mmol) of 2-chloro-5-iodoaniline, dissolved in 80 ml of abs.
DMF, were then slowly added dropwise, and the mixture was stirred at
0° C. for 30 min. 41 ml (303 mmol) of
1-(chloromethyl)-4-methoxybenzene were then slowly added to the reaction
mixture, and the mixture was subsequently warmed to room temperature. The
mixture was stirred at RT overnight and then carefully poured into 150 ml
of ice-water. The organic phase was separated off, and the aqueous phase
was then extracted three more times with diethyl ether. The combined
organic phases were dried over magnesium sulphate. After filtration, the
solvent was removed under reduced pressure. The crude product obtained
was purified by chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 40:1). This gave 59 g of the title compound
(94% of theory).

[0399] Under argon, 7.587 g (15.37 mmol) of
2-chloro-5-iodo-N,N-bis(4-methoxybenzyl)aniline were dissolved in 100 ml
of THF and cooled to -78° C. 7.65 ml (15.27 mmol) of a 2 M
solution of isopropylmagnesium chloride in diethyl ether were then slowly
added dropwise. The reaction solution was then slowly warmed to
-40° C. and stirred at this temperature for 30 min. 2 g (13.97
mmol) of N-methoxy-N,1-dimethylcyclopropanecarboxamide [R. Shintani et
al., Chem. Eur. J., 15 (35), 8692-8694 (2009)], dissolved in 20 ml of
THF, were then slowly added dropwise to the reaction solution. The
reaction mixture obtained was then slowly warmed to room temperature and
stirred at this temperature overnight. 50 ml of an ice-cold saturated
aqueous ammonium chloride solution were then added to the reaction
mixture. After separation of the phases, the aqueous phase was extracted
three more times with ethyl acetate, and the combined organic phases were
dried over magnesium sulphate, filtered and evaporated to dryness. The
crude product obtained was purified chromatographically on silica gel
(mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.977 g (63% of
theory) of the title compound.

[0403] 0.84 ml (3.57 mmol) of tert-butyl (diethoxyphosphoryl)acetate was
added dropwise to a suspension, cooled to 0° C., of 143 mg (60% in
mineral oil, 3.57 mmol) of sodium hydride in 15 ml of THF. After 30 min,
1070 mg (2.38 mmol) of
{3-[bis(4-methoxybenzyl)amino]-4-chloro-phenyl}(1-methylcyclopropyl)metha-
none, dissolved in 10 ml of THF, were added. The cooling bath was removed,
and the reaction mixture was stirred at RT overnight. 50 ml of an
ice-cold saturated aqueous ammonium chloride solution were then added to
the reaction mixture. After separation of the phases, the aqueous phase
was extracted three more times with ethyl acetate, and the combined
organic phases were dried over magnesium sulphate, filtered and
evaporated to dryness. The residue was purified by chromatography on
silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 960
mg of the target product as an E/Z isomer mixture (74% of theory).

[0406] 130 mg (1.58 mmol) of magnesium turnings and a few grains of iodine
were initially charged, 865 mg (1.58 mmol) of tert-butyl
(2E/Z)-3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-3-(1-methylcyclop-
ropyl)acrylate in 10 ml of methanol were added and the mixture was stirred
at room temperature. After about 10 min, there was a weak evolution of
gas combined with a temperature increase. Using an ice bath, the
temperature was kept at 35°-40° C. After the reaction had
ended, ml of a saturated aqueous ammonium chloride solution and 20 ml of
dichloromethane were added to the reaction mixture. The organic phase was
then separated off and the aqueous phase was extracted three more times
with in each case about 10 ml of dichloromethane. The combined organic
phases were dried over magnesium sulphate and concentrated under reduced
pressure. The product was isolated from the residue by preparative
RP-HPLC (mobile phase methanol/water 9:1 isocratic). This gave 159 mg of
the target product (18% of theory).

[0409] 159 mg (0.29 mmol) of tert-butyl
3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-3-(1-methylcyclopropyl)p-
ropanoate were taken up in 7 ml of dichloromethane and 1.2 ml of water.
145 mg (0.64 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
were then added, and the reaction solution was stirred at room
temperature for 2 h. The reaction mixture was then added to 10 ml of
saturated aqueous sodium bicarbonate solution. The phases were separated,
and the aqueous phase was then extracted three more times with in each
case about 10 ml of dichloromethane. The combined organic phases were
dried over magnesium sulphate and concentrated under reduced pressure.
The product was isolated from the residue by preparative RP-HPLC (mobile
phase methanol/water). This gave 31 mg of the target product (34% of
theory).

[0410] LC-MS (Method 7): Rt=1.35 min; m/z=310 (M+H).sup.+.

Example 24A

(4-Chloro-3-nitrophenyl)(cyclopropyl)methanone

##STR00078##

[0412] Under argon and at -10° C., 20 g (110.7 mmol) of
(4-chlorophenyl)(cyclopropyl)methanone were added slowly to 60 ml of
concentrated nitric acid. The reaction mixture was then slowly warmed to
5° C. and stirred at this temperature for 6 h. Carefully, the
reaction solution was then added with stirring to about 100 ml of
ice-water. This resulted in the precipitation of a white solid which was
filtered off with suction and washed repeatedly with water. The solid
obtained in this manner was then dried under high vacuum. This gave 24.3
g (97% of theory) of the desired product.

[0417] 13.5 ml (57.6 mmol) of tert-butyl (diethoxyphosphoryl)acetate were
added dropwise to a suspension, cooled to 0° C., of 2.3 g (60% in
mineral oil, 57.6 mmol) of sodium hydride in 50 ml of THF and 50 ml of
DMF. After 30 min, 10 g (44.3 mmol) of
(4-chloro-3-nitrophenyl)-(cyclopropyl)methanone were added a little at a
time, the cooling bath was removed and the reaction mixture was stirred
at RT overnight. 50 ml of an ice-cooled saturated aqueous ammonium
chloride solution were then added to the reaction mixture. After
separation of the phases, the aqueous phase was extracted three more
times with ethyl acetate and the combined organic phases were dried over
magnesium sulphate, filtered and concentrated to dryness. The residue was
purified by chromatography on silica gel (mobile phase
cyclohexane→cyclohexane/ethyl acetate 40:1). This gave 13.4 g of
the target product as an E/Z isomer mixture (93% of theory).

[0422] 200 mg (0.62 mmol) of tert-butyl
(2E/Z)-3-(4-chloro-3-nitrophenyl)-3-cyclopropylacrylate were dissolved in
12 ml of ethyl acetate, and 20 mg (0.06 mmol) of platinum (10% on carbon)
were added. The reaction mixture was stirred at RT under an atmosphere of
hydrogen at atmospheric pressure for 12 hours. The reaction mixture was
then filtered off with suction through kieselguhr, and the filtrate was
concentrated. The crude product was purified by chromatography on silica
gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave 96 mg (52.1%
of theory) of the target compound.

[0439] 384 mg (1.12 mmol) of tert-butyl
(2E/Z)-3-(4-chloro-3-nitrophenyl)-3-(1-fluorocyclopropyl)-acrylate were
dissolved in 12 ml of ethyl acetate, and 38 mg (0.17 mmol) of
platinum(IV) oxide were added. The reaction mixture was stirred at RT
under an atmosphere of hydrogen at atmospheric pressure overnight. The
reaction mixture was then filtered off with suction through kieselguhr
and the filtrate was concentrated. The product was isolated from the
residue by preparative RP-HPLC (mobile phase methanol/water). This gave
68 mg (19% of theory) of the target compound.

[0440] LC-MS (Method 7): Rt=1.24 min; m/z=314 (M+H).sup.+.

Example 33A

(+/-)-tert-Butyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylpropanoate

##STR00086##

[0441] Method A:

[0442] 133 mg (9.432 mmol) of tert-butyl
3-(3-amino-4-chlorophenyl)-3-cyclobutylidenepropanoate were dissolved in
20 ml of ethyl acetate. The solution was deoxygenated with argon, and 30
mg of 10% palladium on carbon were added. At RT, the reaction mixture was
stirred under an atmosphere of hydrogen at atmospheric pressure
overnight. The mixture was then filtered off through Celite, and the
filtrate was concentrated under reduced pressure. The product was
isolated from the residue by preparative RP-HPLC (mobile phase
acetonitrile/water). This gave 67 mg of the target compound (50% of
theory).

[0445] At RT, a solution of 189 mg (0.614 mmol) of tert-butyl
3-(3-amino-4-chlorophenyl)-3-cyclobutylacrylate in 0.9 ml of methanol was
added to 39 mg (1.60 mmol) of magnesium turnings and a few grains of
iodine. The dark reaction mixture was stirred at RT overnight and then
added to water and extracted with ethyl acetate. The organic phase was
washed with saturated sodium bicarbonate solution and saturated sodium
chloride solution, dried over magnesium sulphate and concentrated under
reduced pressure. The product was isolated from the residue by
preparative RP-HPLC. This gave 57.7 mg of the target compound (30.3% of
theory).

[0447] Under argon, 2.53 g (8.17 mmol) of ethyl
(2E/Z)-3-(4-chloro-3-nitrophenyl)-3-cyclopropyl-2-methylacrylate were
dissolved in 10 ml of dioxane, and 9.22 g (40.84 mmol) of tin(II)
chloride dihydrate were added. The reaction mixture was then heated to
70° C. and stirred at this temperature overnight. After cooling to
room temperature, about 20 ml of ethyl acetate were added and the
reaction mixture was then added to about 20 ml of a 10% strength aqueous
potassium fluoride solution. The resulting mixture was stirred vigorously
for 10 min. The phases were separated, and the aqueous phase was then
extracted two more times with in each case 10 ml of ethyl acetate. The
combined organic phases were washed with about 50 ml of a saturated
sodium chloride solution, dried over magnesium sulphate and concentrated
under reduced pressure. This gave 2.2 g (96% of theory) of the target
compound which was used without further purification for the next step.

[0450] Under argon and at RT, a solution of 2.2 g (7.86 mmol) of ethyl
(2E/Z)-3-(3-amino-4-chlorophenyl)-3-cyclopropyl-2-methylacrylate in 20 ml
of methanol was added to 497 mg (20.45 mmol) of magnesium turnings and a
few grains of iodine. The dark reaction mixture was stirred at RT
overnight and then allowed to stand under argon for two days. The
reaction solution was then diluted with ethyl acetate, and 1 M
hydrochloric acid was added. The mixture was stirred for 5 min and then
adjusted to pH 8-9 using saturated sodium bicarbonate solution. The
organic phase was separated off, and the aqueous phase was extracted two
more times with ethyl acetate. The combined organic phases were washed
with saturated sodium chloride solution, dried over magnesium sulphate
and concentrated under reduced pressure. The crude product was purified
by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate
100:1→50:1→20:1). This gave 1.38 g (62% of theory) of the
target compound.

[0451] LC-MS (Method 5): Rt=1.13 min; m/z=282/284 (M+H).sup.+.

Example 36A

Dimethyl (3-methylbutan-2-ylidene)malonate

##STR00089##

[0453] Under argon and at 0° C., 10 g (75.7 mmol) of dimethyl
malonate in 20 ml of chloroform were slowly added dropwise to a solution
of 16.6 ml (151.4 mmol) of titanium tetrachloride in 60 ml of chloroform.
After the addition had ended, the reaction solution was stirred at
0° C. for another 30 min. At 0° C., 6.52 g (75.7 mmol) of
3-methyl-2-butanone in 20 ml of chloroform were then added dropwise. The
reaction mixture was slowly warmed to room temperature and stirred at
this temperature for 4 h. The reaction solution was then once more cooled
to 0° C., and 30.6 ml (378.5 mmol) of pyridine in 20 ml of
chloroform were added. After the addition had ended, the solution was
warmed to room temperature and stirred at this temperature overnight. The
reaction solution was then once more cooled to 0° C., and 50 ml of
water were added slowly. The resulting phases were separated, and the
aqueous phase was extracted two more times with in each case about 50 ml
of dichloromethane. The combined organic phases were washed with
saturated sodium bicarbonate solution and with saturated sodium chloride
solution, dried over magnesium sulphate and concentrated under reduced
pressure. The crude product was purified by chromatography on silica gel
(mobile phase cyclohexane/ethyl acetate 20:1). This gave 9.4 g (62% of
theory) of the target compound.

[0458] Under argon, 6.2 g (26 mmol) of 1-chloro-4-iodobenzene were
dissolved in 50 ml of THF and cooled to -78° C. 24 ml (31.2 mmol)
of a 1.3 M solution of isopropylmagnesium chloride×lithium chloride
in THF were then slowly added dropwise. The reaction solution was then
slowly warmed to -40° C. and stirred at this temperature for 2 h.
The reaction solution was then warmed to -10° C., and 495 mg (2.6
mmol) of copper(I) iodide were added. 5 g (24.97 mmol) of dimethyl
(3-methylbutan-2-ylidene)malonate, dissolved in 30 ml of THF, were then
slowly added dropwise to the reaction solution. The resulting reaction
mixture was slowly warmed to room temperature and stirred at this
temperature for 1 h. The mixture was then cooled to 0° C., and
ice-cold 1 M hydrochloric acid (pH ˜2) was added carefully. The
phases were separated, the aqueous phase was then extracted three more
times with ethyl acetate and the combined organic phases were dried over
magnesium sulphate, filtered and concentrated to dryness. The resulting
crude product was initially pre-purified chromatographically on silica
gel (mobile phase cyclohexane/ethyl acetate 20:1). The product was then
re-purified by preparative RP-HPLC (mobile phase methanol/water). This
gave 3.38 g (42% of theory) of the target compound.

[0462] 627 mg (1.11 mmol) of dimethyl
(1-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-1-cyclo-propylethyl)mal-
onate were taken up in 60 ml of dichloromethane and 15 ml of water. 553 mg
(2.44 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) were then
added, and the reaction mixture was stirred at room temperature for 2
hours. The reaction mixture was then added to about 50 ml of saturated
aqueous sodium bicarbonate solution. The phases were separated, and the
aqueous phase was extracted three more times with in each case about 10
ml of dichloromethane. The combined organic phases were dried over
magnesium sulphate and concentrated under reduced pressure. The product
was isolated from the residue by preparative RP-HPLC (mobile phase
methanol/water). This gave 283 mg of the target product (78% of theory).

[0466] 3.38 g (10.81 mmol) of dimethyl
[2-(4-chlorophenyl)-3-methylbutan-2-yl]malonate, 0.92 g (21.61 mmol) of
lithium chloride and 0.2 ml of water in 10 ml of DMSO were heated under
reflux for 4 h. After cooling, about 50 ml of diethyl ether were added to
the reaction solution, and the phases were separated. The organic phase
was washed twice with water, dried over magnesium sulphate and
concentrated under reduced pressure. The crude product was purified by
chromatography on silica gel (mobile phase cyclohexane/ethyl acetate
10:1). This gave 2.3 g (84% of theory) of the target compound.

[0471] 2.3 g (9.03 mmol) of methyl
3-(4-chlorophenyl)-3,4-dimethylpentanoate were dissolved in 50 ml of
dichloromethane and cooled to 0° C. 1.44 g (10.8 mmol) of
nitronium tetrafluoroborate were then added a little at a time. After the
addition had ended, the reaction solution was initially stirred at
0°-10° C. for 1 h. The mixture was then slowly warmed to
room temperature and stirred at this temperature for another 2 h. The
reaction mixture was then added to about 50 ml of water, the phases were
separated and the organic phase was dried over magnesium sulphate. The
solution was concentrated by evaporation and the residue obtained was
then purified by chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 20:1). This gave 2.3 g (85% of theory) of the
target compound.

[0476] 1.79 g (5.74 mmol) of methyl
3-(4-chloro-3-nitrophenyl)-3-cyclobutylbutanoate were dissolved in 50 ml
of ethyl acetate, and about 150 mg of 10% palladium on carbon were added.
At RT, the reaction mixture was stirred vigorously under an atmosphere of
hydrogen at atmospheric pressure overnight. The mixture was then filtered
through Celite, and the filtrate obtained was evaporated to dryness. The
crude product was purified by chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 20:1). This gave 1.36 g of the target product
(84% of theory).

[0507] 60 g (295.5 mmol) of 3-chloro-1-(4-chlorophenyl)propan-1-one were
dissolved in 900 ml of acetonitrile. With ice bath cooling, 41.2 ml
(295.5 mmol) of triethylamine were then slowly added dropwise to the
solution (exothermal reaction). After the addition had ended, the
reaction solution was stirred at room temperature for 4 h. About one
litre of water, one litre of ethyl acetate and about 250 ml of saturated
sodium chloride solution were then added to the reaction mixture. The
phases were separated, the organic phase was then dried over magnesium
sulphate and filtered and the filtrate was concentrated to dryness. The
crude product obtained was purified by chromatography on silica gel
(about 1.3 kg) (mobile phase cyclohexane/ethyl acetate 6:1). This gave 45
g of the target product (91% of theory).

[0510] Under argon, 91 g (546 mmol) of 1-(4-chlorophenyl)prop-2-en-1-one,
2.293 g (54.6 mmol) of sodium fluoride and 2.41 g (10.92 mmol) of
2,6-di-tert-butyl 4-methylphenol were heated in a 3 litre three-necked
flask to 110° C. and stirred at this temperature for 5 min. At an
internal temperature of 110°-125° C., 183 ml (928.5 mmol)
of trimethylsilyl 2,2-difluoro-2-(fluorosulphonyl)acetate were then
slowly added dropwise over a period of 30-35 min to the solution
(careful: evolution of gas). After the addition and the evolution of gas
had ended, the reaction solution was stirred for another 20 min. After
cooling, the reaction mixture was taken up in several litres of ethyl
acetate and extracted with saturated aqueous sodium bicarbonate solution.
The phases were separated, the organic phase was then dried over
magnesium sulphate and filtered and the filtrate was concentrated to
dryness. The crude product obtained was purified by chromatography on
silica gel (about 2 kg) (mobile phase cyclohexane/ethyl acetate 10:1).
This gave 63 g of the target product (53% of theory).

[0513] 2.2 g (60% in mineral oil, 55 mmol) of sodium hydride were stirred
with 20 ml of THF and then filtered off with suction, and the filtercake
was washed with 20 ml of THF. Under argon, the sodium hydride purified in
this manner was introduced into 200 ml of THF. The mixture was then
cooled to 0° C., and 10.1 g (55 mmol) of methyl
(diethoxyphosphoryl)acetate, dissolved in 10 ml of THF, were added. After
warming to room temperature, the solution was stirred for another 1 h.
5.15 g (19.73 mmol) of (4-chlorophenyl)(2,2-difluorocyclopropyl)methanone
in 50 ml of THF were then added dropwise. After the addition had ended,
the solution was heated to reflux and stirred for 2 h. The solution was
then cooled to 5° C., and the mixture was poured into 400 ml of
ice-water. The phases were separated, and the aqueous phase was then
extracted three more times with tert-butyl methyl ether. The combined
organic phases were washed successively with 1 M hydrochloric acid and
saturated sodium chloride solution, dried over sodium sulphate, filtered
and concentrated to dryness. The crude product obtained was purified by
chromatography on silica gel (mobile phase cyclohexane/ethyl acetate
20:1→8:1). The E/Z isomers were isolated in separated form. This
gave 2.23 g (37% of theory) of methyl
(2E)-3-(4-chlorophenyl)-3-(2,2-difluoro-cyclopropyl)acrylate and 1.6 g
(24.4% of theory) of methyl
(2Z)-3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)acrylate.

[0517] 1000 mg (3.67 mmol) of methyl
(2Z)-3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)acrylate were
dissolved in 75 ml of ethyl acetate and hydrogenated in a continuous-flow
hydrogenation apparatus (H-Cube, from Thales Nano, Budapest) fitted with
a catalyst cartridge (10% palladium on carbon) at a flow rate of 1 ml/min
and at room temperature and atmospheric pressure using hydrogen. After
the reaction had gone to completion, the reaction mixture was
concentrated under reduced pressure. This gave 980 mg of a product
mixture consisting of methyl
3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)propanoate and methyl
3-(4-chlorophenyl)-5,5-difluorohexanoate as a colourless oil.

[0520] 610 mg of the mixture consisting of methyl
3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)-propanoate and methyl
3-(4-chlorophenyl)-5,5-difluorohexanoate (Example 57A) were dissolved in
12 ml of dichloromethane and cooled to 0° C. 351 mg (2.65 mmol) of
nitroniumtetrafluoroborate were then added a little at a time. After the
addition had ended, the reaction solution was stirred at
0°-10° C. for 1 h. The mixture was then slowly warmed to
room temperature and stirred at this temperature for a further 2 h. The
reaction mixture was then added to about 20 ml of water, the phases were
separated and the organic phase was dried over magnesium sulphate. The
solution was concentrated by evaporation and the residue obtained was
then purified by chromatography on silica gel (mobile phase
cyclohexane/ethyl acetate 20:1). This gave 637 mg of the mixture of the
two target compounds.

[0523] 640 mg of the mixture consisting of methyl
3-(4-chloro-3-nitrophenyl)-3-(2,2-difluorocyclopropyl)propanoate and
methyl 3-(4-chloro-3-nitrophenyl)-5,5-difluorohexanoate (Example 58A)
were dissolved in 40 ml of ethyl acetate, and 106 mg of palladium on
carbon (10%) were added. The reaction mixture was stirred vigorously
under an atmosphere of hydrogen at atmospheric pressure overnight. The
mixture was then filtered through Celite, and the filtrate obtained was
evaporated to dryness. The crude product was purified by chromatography
on silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 361
mg of the mixture of the two target compounds.

[0524] LC-MS (Method 5): Rt=0.98 min; m/z=290/292 (M+H).sup.+.

Example 60A

(+)-Ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate

##STR00111##

[0526] At room temperature, 133 ml (1.82 mol) of thionyl chloride were
added slowly to 287 g (1.65 mol) of (3R)-4,4,4-trifluoro-3-methylbutanoic
acid [A. Gerlach and U. Schulz, Speciality Chemicals Magazine 24 (4),
37-38 (2004); CAS Acc.-No. 142:179196] in 580 ml of ethanol. The reaction
solution was then heated to 80° C. and stirred at this temperature
for 2 h. The mixture was then cooled to room temperature, 250 ml of water
were added slowly and the mixture was extracted three times with in each
case 150 ml of tert-butyl methyl ether. The combined organic phases were
dried over sodium sulphate. After filtration the solvent was removed
under reduced pressure at 30° C. and a pressure of 300 mbar. The
crude product was then distilled at 100 mbar and a head temperature of
65° C. This gave 225.8 g (113 mol, 74% of theory) of the title
compound as a colourless liquid.

[0531] Under argon 196.9 mg (0.88 mmol) of palladium(II) acetate and 724.8
mg (1.84 mmol) of 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl
were initially charged in 50 ml of anhydrous toluene. 43.8 ml (43.8 mmol)
of a 1 M solution of lithium hexamethyldisilazide in THF were added
slowly, and the reaction solution was then stirred at RT for 10 min. The
reaction solution was then cooled to -10° C., 7 g (38.0 mmol) of
(+/-)-ethyl 4,4,4-trifluoro-3-methylbutanoate were added slowly and the
mixture was stirred at -10° C. for 10 min. 5 g (29.2 mmol) of
4-bromotoluene, dissolved in 50 ml of toluene, were then added dropwise,
and the reaction solution was warmed first to RT and then heated to
80° C. The mixture was stirred at this temperature for 2 h and
then cooled to RT and stirred overnight. After the reaction had ended
(monitored by TLC; mobile phase cyclohexane/dichloromethane 2:1), the
reaction mixture was filtered through kieselguhr, the residue was washed
repeatedly with ethyl acetate and dichloromethane and the combined
filtrates were concentrated under reduced pressure. The crude product
obtained was purified chromatographically on silica gel (mobile phase
petroleum ether/dichloromethane 4:1→3:1). This gave 3.91 g (14.3
mmol, 48.8% of theory) of the title compound as a colourless liquid.

[0535] Preparation of solution A: Under argon, 16.3 ml of a 1 M solution
of lithium hexamethyldisilazide in toluene were cooled to -10° C.
to -20° C. (cooling with acetone/dry ice), and 2 g (10.86 mmol) of
(+)-ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate, dissolved in 10 ml of
toluene, were added slowly; during the addition, it was made sure that a
temperature of -10° C. was not exceeded. The solution was then
stirred for another 10 min at at most -10° C.

[0536] Preparation of solution B: Under argon, 2.415 g (14.12 mmol) of
4-bromotoluene were dissolved at RT in 10 ml of toluene, and 73 mg (0.33
mmol) of palladium(II) acetate and 269 mg (0.68 mmol) of
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl were added. The
solution was stirred at RT for 10 min.

[0537] First, the cooling bath was removed from solution A. Solution B was
then slowly added dropwise to solution A, which was still cold. The
combined solutions were then slowly warmed to RT and stirred at this
temperature for 1 h. The reaction solution was then heated to 80°
C. (internal temperature) and stirred at this temperature for 3 h. The
reaction solution was then slowly cooled to RT and stirred for another 12
h. Finally, the reaction mixture was filtered through kieselguhr, the
residue was washed repeatedly with toluene and the combined filtrates
were concentrated under reduced pressure. The crude product obtained was
purified chromatographically on silica gel (mobile phase
cyclohexane/dichloromethane 10:1→4:1). This gave 2.35 g (79% of
theory) of the title compound.

[0541] Preparation of solution A: Under argon, 163.9 ml of a 1 M solution
of lithium hexamethyldisilazide in toluene were cooled to -10° C.
to -20° C. (cooling using acetone/dry ice), and g (108.6 mmol) of
(+)-ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate, dissolved in 150 ml of
toluene, were added slowly; during the addition care was taken that a
temperature of -10° C. was not exceeded. The solution was then
stirred for another 10 min at at most -10° C.

[0542] Preparation of solution B: Under argon, 27.03 g (141.2 mmol) of
1-bromo-4-chlorobenzene were dissolved at RT in 100 ml of toluene, and
731 mg (3.26 mmol) of palladium(II) acetate and 2.693 g (6.84 mmol) of
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl were added. The
solution was stirred at RT for 10 min.

[0543] First, the cooling bath was removed from solution A. Solution B was
then slowly added dropwise to solution A, which was still cold. The
combined solutions were then slowly warmed to RT and stirred at this
temperature for 1 h. The reaction solution was then heated to 80°
C. (internal temperature) and stirred at this temperature for 3 h. The
reaction solution was then slowly cooled to RT and stirred for another 12
h. The reaction mixture was finally filtered through kieselguhr, the
residue was washed repeatedly with toluene and the combined filtrates
were concentrated under reduced pressure. The crude product obtained was
purified chromatographically on silica gel (mobile phase
cyclohexane/dichloromethane 4:1). This gave 27.4 g (92.98 mmol, 86% of
theory) of the title compound as a yellow oil in a diastereomer ratio of
3:1.

[0547] 24.4 ml (24.4 mmol) of a 1 M solution of lithium
hexamethyldisilazide in toluene were cooled to -10° C., and a
solution of 3.0 g (16.29 mmol) of (+)-ethyl
(3R)-4,4,4-trifluoro-3-methylbutanoate in ml of abs. toluene was added
dropwise. The mixture was stirred for 10 min. At -10° C., a
solution, prepared beforehand, of 3.92 g (21.18 mmol) of
1-bromo-4-ethylbenzene, 110 mg (0.49 mmol) of palladium(II) acetate and
404 mg (1.03 mmol) of
2'-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl in 20 ml of abs.
toluene was then added dropwise. The resulting reaction mixture was then
stirred first at RT for 1 h and then at 80° C. for 3 h. The
mixture was then concentrated under reduced pressure and the residue was
taken up in ethyl acetate and added to water. The aqueous phase was
re-extracted with ethyl acetate, and the combined organic phases were
washed with saturated ammonium chloride solution and saturated sodium
chloride solution, dried over magnesium sulphate and concentrated under
reduced pressure. The residue gave, after chromatography on silica gel
(mobile phase first cyclohexane, then gradient cyclohexane/ethyl acetate
200:1→50:1), 3.051 g of the title compound (64.9% of theory,
diastereomer ratio about 3:1).

[0565] 2.25 g (8.2 mmol) of ethyl
4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate, 1.53 g (8.6 mmol)
of N-bromosuccinimide and 67 mg (0.41 mmol) of
2,2'-azobis-(2-methylpropanenitrile) in 36 ml of trichloromethane were
stirred under reflux overnight. After the reaction had gone to
completion, the succinimide was filtered off, the filter residue was
washed with dichloromethane and the filtrate was concentrated under
reduced pressure. The crude product was purified chromatographically on
silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave 2.667
g (7.5 mmol, 92% of theory) of a yellowish oil.

[0568] 529 mg (2.78 mmol) of copper(I) iodide and 4 g (20.82 mmol) of
methyl 2,2-difluoro-2-(fluorosulphonyl)acetate were added to 3.77 g
(10.67 mmol) of ethyl
2-[4-(bromo-methyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate in 40 ml of
1-methylpyrrolidin-2-one, and the mixture was stirred at 80° C.
overnight. After the reaction had ended, the reaction solution was slowly
poured into 100 ml of ice-water. The mixture obtained was then extracted
three times with diethyl ether. The combined organic phases were dried
over magnesium sulphate. After filtration, the solvent was removed under
reduced pressure. The crude product obtained was purified
chromatographically on silica gel (mobile phase
cyclohexane/dichloromethane 4:1). This gave 1.48 g (4.32 mmol, 41% of
theory) of the title compound as a yellowish oil.

[0572] Under argon, 14.8 ml (105.6 mmol) of diisopropylamine were
initially charged in 150 ml of THF, the mixture was cooled to -30°
C. and 42.3 ml (105.75 mmol) of a 2.5 M solution of n-butyllithium in
hexane were added slowly. The reaction solution was then warmed to
-20° C., 15 g (81.25 mmol) of methyl (4-chlorophenyl)acetate,
dissolved in 90 ml of THF, were added slowly and the mixture was stirred
at this temperature for 2 h. The reaction solution then cooled to
-78° C., and 7.2 ml (86.1 mmol) of 2-cyclopenten-1-one, dissolved
in 60 ml of THF, were added slowly. After the addition had ended, the
solution was stirred at -78° C. for another hour. After TLC
(mobile phase cyclohexane/ethyl acetate 9:1), saturated aqueous ammonium
chloride solution was added and the product was taken up in ethyl
acetate. The aqueous phase was extracted twice with ethyl acetate. The
combined organic phases were dried over magnesium sulphate. After
filtration, the solvent was removed under reduced pressure. The crude
product was purified chromatographically on silica gel (mobile phase
cyclohexane/ethyl acetate 4:1). This gave 15.65 g (58.67 mmol, 72% of
theory) of the title compound as a yellowish oil.

[0576] Under argon, 82.5 ml (82.14 mmol) of a 50% strength solution of
1,1'-[(trifluoro-λ4-sulphanyl)-imino]bis(2-methoxyethane)
(Desoxofluor) in THF, diluted with 200 ml of toluene, were initially
charged and cooled to 5° C., and 744 μl (5.87 mmol) of a 1 M
solution of boron trifluoride/diethyl ether complex were added slowly.
The mixture was stirred at 5° C. for 2 h. 15.65 g (58.67 mmol) of
methyl (4-chlorophenyl)(3-oxocyclopentyl)acetate, dissolved in 200 ml of
toluene, were then added slowly, and the reaction solution was
subsequently warmed to 55° C. and stirred at this temperature for
60 h. The reaction mixture was then added to a mixture, cooled to
0° C., consisting of 100 ml of toluene and 100 ml of 2 M aqueous
sodium hydroxide solution. The organic phase was separated off, and the
aqueous phase was extracted three more times with ethyl acetate. The
combined organic phases were dried over sodium sulphate. After
filtration, the solvent was removed under reduced pressure. The crude
product was purified chromatographically on silica gel (mobile phase
cyclohexane/ethyl acetate 7:1). This gave 13.24 g (45.86 mmol, 78% of
theory) of the title compound as a colourless oil.

[0584] 16.28 g (55.24 mmol) of ethyl
(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoate were dissolved
in 220 ml of dioxane, and 110.5 ml of 1 N aqueous sodium hydroxide
solution were added. The reaction was stirred at 50° C. for 3 h.
The dioxane was then removed on a rotary evaporator, and the aqueous
solution that remained was, with ice-cooling, neutralized with 1 N
hydrochloric acid (˜pH 7). The precipitated solid was filtered off
with suction and dried under high vacuum at 40° C. overnight. This
gave 9.2 g of the target compound as a slightly beige solid (fraction 1;
62.5% of theory, 94% de). The filtrate was acidified by further addition
of 1 N hydrochloric acid (˜pH 1) and stirred overnight. Once more,
the precipitated solid was filtered off with suction and dried under high
vacuum at 40° C. overnight. This gave a further 3.46 g of the
target compound as a white solid (fraction 2; contaminated with 10% of
the second diastereomer). The aqueous filtrate that remained was
repeatedly extracted with dichloromethane, and the combined organic
phases were dried over magnesium sulphate and concentrated under reduced
pressure. This gave another 2.44 g of the target compound as a colourless
oil (fraction 3; contaminated with 15% of the second diastereomer).
Fractions 2 and 3 were finally combined and re-purified
chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate
10:1). This gave 3.7 g of the target compound as a white solid (fraction
4; 25% of theory, >95% de).

[0591] 3.0 g of ethyl
(3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoate (purity about
88%, about 9.16 mmol; diastereomer mixture) were dissolved in the mixture
of in each case 12.4 ml of methanol, THF and water, and 5.49 g (137.35
mmol) of sodium hydroxide were added a little at a time. The reaction
mixture was stirred at 40° C. for 9 h. After cooling, the volatile
solvents were substantially removed under reduced pressure and the
residue was diluted with water. The mixture was acidified by addition of
hydrochloric acid, and the aqueous phase was extracted three times with
ethyl acetate. The combined organic phases were dried over sodium
sulphate, and concentrated under reduced pressure, and the residue was
dried under high vacuum. This gave 2.61 g of the title compound as a
crude product which was not purified any further (diastereomer ratio
about 9:1).

[0629] 328 mg (1.23 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were
dissolved in 17.5 ml of dichloromethane, 263 mg (1.97 mmol) of
1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was
stirred at room temperature for 30 min. 299 μl (3.7 mmol) of pyridine
and 315 mg (1.23 mmol) of methyl
3-(3-amino-4-chlorophenyl)-4-methyl-pentanoate (enantiomer 1; Example
17A) were then added, and the reaction mixture was stirred overnight. The
reaction mixture was then concentrated under reduced pressure and the
crude product obtained was purified directly by preparative RP-HPLC
(mobile phase methanol/water 80:20). This gave 237 mg of the target
compound (38% of theory).

[0634] 255 mg (0.96 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were
dissolved in 14 ml of dichloromethane, 205 mg (1.53 mmol) of
1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was
stirred at room temperature for 30 min. 232 μl (2.87 mmol) of pyridine
and 245 mg (0.96 mmol) of methyl
3-(3-amino-4-chlorophenyl)-4-methylpentanoate (enantiomer 2; Example 18A)
were then added, and the reaction mixture was stirred overnight. The
reaction mixture was then concentrated under reduced pressure and the
crude product obtained was purified directly by preparative RP-HPLC
(mobile phase methanol/water 80:20). This gave 228 mg of the target
compound (47% of theory).

[0639] 45 mg (0.17 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were
dissolved in 1 ml of dichloromethane, 36 mg (0.27 mmol) of
1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was
stirred at room temperature for 30 min. 411 (0.51 mmol) of pyridine and
50 mg (0.17 mmol) of tert-butyl
3-(3-amino-4-chlorophenyl)-3-cyclo-propylpropanoate (enantiomer 1;
Example 30A), dissolved in 1 ml of dichloromethane, were then added, and
the reaction mixture was stirred for another 1 h. The reaction mixture
was then concentrated under reduced pressure and the crude product
obtained was directly purified chromatographically on silica gel (mobile
phase cyclohexane/ethyl acetate 20:1). This gave 78 mg of the target
compound (85% of theory).

[0642] 119 mg (0.45 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were
dissolved in 2 ml of dichloromethane, 95 mg (0.71 mmol) of
1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was
stirred at room temperature for 30 min. 108 μl (1.34 mmol) of pyridine
and 132 mg (0.45 mmol) of tert-butyl
3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate (enantiomer 2; Example
31A), dissolved in 2 ml of dichloromethane, were then added, and the
reaction mixture was stirred for another 1 h. The reaction mixture was
then concentrated under reduced pressure and the crude product obtained
was directly purified chromatographically on silica gel (mobile phase
cyclohexane/ethyl acetate 20:1). This gave 206 mg of the target compound
as a colourless oil (85% of theory).

[0647] 330 mg (1.24 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were
dissolved in 10 ml of dichloromethane, 264 mg (1.98 mmol) of
1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was
stirred at room temperature for 30 min. 3001 (3.71 mmol) of pyridine and
360 mg of the mixture consisting of methyl
3-(3-amino-4-chlorophenyl)-3-(2,2-difluorocyclopropyl)propanoate and
methyl 3-(3-amino-4-chlorophenyl)-5,5-difluorohexanoate (Example 59A),
dissolved in 1 ml of dichloromethane, were then added, and the reaction
mixture was stirred for a further 1 h. The reaction mixture was then
concentrated under reduced pressure and the crude product obtained was
directly purified chromatographically on silica gel (mobile phase
cyclohexane/ethyl acetate 20:1). This gave 479 mg of the mixture of the
two target compounds.

[0675] A solution of 76 mg (0.29 mmol) of
(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid, 45 mg
(0.13 mmol) of tert-butyl
3-(3-amino-4-chlorophenyl)-3-(3,3-difluorocyclobutyl)-propanoate, 119 mg
(0.31 mmol) of O-(1H-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) and 0.51 ml of pyridine in 1 ml of DMF was
stirred at room temperature overnight. After the reaction had ended, the
mixture was directly, without further work-up, separated into its
components by preparative HPLC. This gave 19 mg (25% of theory) of the
title compound as a colourless oil.

[0676] LC-MS (Method 5): Rt=1.47 min; m/z=592/594 (M-H).sup.-.

[0677] The compounds listed in the table below were prepared in an
analogous manner:

[0679] 11.23 g (87.1 mmol) of zinc/copper pair were taken up in 50 ml of
diethyl ether, and 6.76 ml (92.9 mmol) of chloroiodomethane were added at
room temperature. 5.84 ml (58.1 mmol) of 3-methylbut-3-en-1-ol, dissolved
in 10 ml of diethyl ether, were then added dropwise. After the addition
had ended, the reaction mixture was heated to 40° C. and stirred
at this temperature overnight. After cooling, the reaction was filtered
off with suction through kieselguhr, and the kieselguhr was washed
repeatedly with diethyl ether. The combined filtrates were washed with
saturated aqueous sodium bicarbonate solution and with water, dried over
magnesium sulphate and then concentrated to dryness under reduced
pressure. The residue obtained was purified by chromatography on silica
gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.58 g (62%
of theory) of the title compound.

[0684] 187 mg (0.58 mmol) of tert-butyl
(2E/Z)-3-(3-amino-4-chlorophenyl)-4-(1-methylcyclopropyl)but-2-enoate
were dissolved in 10 ml of ethyl acetate, and 11 mg (0.06 mmol) of
platinum(IV) oxide were added. At RT, the reaction mixture was stirred
under an atmosphere of hydrogen at atmospheric pressure overnight.
Another 11 mg (0.06 mmol) of platinum(IV) oxide were added, and the
mixture was then once more stirred at RT under an atmosphere of hydrogen
at atmospheric pressure overnight. The reaction mixture was then filtered
off with suction through kieselguhr, and the filtrate was concentrated.
This gave 36 mg (19% of theory) of the target compound.

[0689] 4 ml of concentrated acetic acid and 2 ml of concentrated
hydrochloric acid were added to 225 mg (0.45 mmol) of methyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methyl-butan-
oyl]amino}phenyl)-4-methylpentanoate (diastereomer 1; Example 96A). The
reaction mixture was stirred at 100° C. for 2 h. After cooling,
the reaction mixture was added to ice-water, and the crystals formed were
filtered off with suction. The crystals were washed twice with water and
then dried in a high vacuum drying cabinet at 40° C. overnight.
This gave 193 mg (88% of theory) of the title compound as a white solid.

[0694] 4 ml of concentrated acetic acid and 2 ml of concentrated
hydrochloric acid were added to 218 mg (0.43 mmol) of methyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methyl-butan-
oyl]amino}phenyl)-4-methylpentanoate (diastereomer 2; Example 97A). The
reaction mixture was stirred at 100° C. for 2 h. After cooling,
the reaction mixture was added to ice-water, and the crystals formed were
filtered off with suction. The crystals were washed twice with water and
then dried in a high vacuum drying cabinet at 40° C. overnight.
This gave 188 mg (89% of theory) of the title compound as a white solid.

[0700] 78 mg (0.14 mmol) of tert-butyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutano-
yl]amino}phenyl)-3-cyclopropylpropanoate (diastereomer 2; Example 99A)
were dissolved in 10 ml of dichloromethane, and 0.33 ml (4.3 mmol) of
trifluoroacetic acid was added at RT. The reaction mixture was stirred at
RT for 4 h and then diluted with 10 ml of water. The phases were
separated, and the aqueous phase was then extracted three more times with
dichloromethane. The combined organic phases were dried over magnesium
sulphate and concentrated under reduced pressure. The crude product
obtained in this manner was purified by preparative RP HPLC (mobile phase
methanol/water 8:2 isocratic). This gave 56 mg of the target compound
(81% of theory).

[0705] 250 mg (0.47 mmol) of ethyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methyl-butan-
oyl]amino}phenyl)-3-cyclopropyl-2-methylpropanoate (diastereomer mixture;
Example 129A) were dissolved in a mixture of 1.0 ml of methanol, 0.5 ml
of THF and 0.5 ml of water, and 40 mg (0.94 mmol) of lithium hydroxide
monohydrate were added at 0° C. The mixture was stirred initially
at 0° C. for 1 h and then at RT overnight. Another 40 mg (0.94
mmol) of lithium hydroxide monohydrate were then added, and the reaction
solution was warmed to 50° C. After further stirring at this
temperature overnight, 1 ml of methanol was metered into the reaction
mixture, and the mixture was stirred at 60° C. for a further 12 h.
The solution was then diluted with water and acidified with 1 N
hydrochloric acid (pH about 2). The aqueous phase was extracted three
times with ethyl acetate. The combined organic phases were dried over
magnesium sulphate and concentrated under reduced pressure. This gave 204
mg (86% of theory) of the title compound as a diastereomer mixture.

[0709] 114 mg (0.21 mmol) of methyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutano-
yl]amino}phenyl)-3-(2,2-difluorocyclopropyl)propanoate (isomer 1; Example
124A) were dissolved in a mixture of 2 ml of dioxane and 1 ml of water,
and 27 mg (0.64 mmol) of lithium hydroxide monohydrate were added. The
mixture was stirred at RT overnight. The solution was then diluted with
water and acidified with 1 N hydrochloric acid (pH about 2). The
precipitated solid was filtered off with suction and dried under high
vacuum overnight. This gave 89 mg (80% of theory) of the title compound
as a diastereomer mixture in the form of a white solid.

[0713] 115 mg (0.21 mmol) of methyl
3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutano-
yl]amino}phenyl)-3-(2,2-difluorocyclopropyl)propanoate (isomer 2; Example
125A) were dissolved in a mixture of 2 ml of dioxane and 1 ml of water,
and 27 mg (0.64 mmol) of lithium hydroxide monohydrate were added. The
mixture was stirred at RT overnight. The solution was then diluted with
water and acidified with 1 N hydrochloric acid (pH about 2). The aqueous
phase was extracted three times with dichloromethane. The combined
organic phases were dried over magnesium sulphate and concentrated under
reduced pressure. This gave 101 mg (90% of theory) of the title compound
as a diastereomer mixture in the form of a colourless oil.

[0739] Investigations on the stimulation of recombinant soluble guanylate
cyclase (sGC) by the compounds according to the invention with and
without sodium nitroprusside, and with and without the haem-dependent sGC
inhibitor 1H-1,2,4-oxadiazolo[4,3a]quinoxalin-1-one (ODQ), are carried
out by the method described in detail in the following reference: M.
Hoenicka, E. M. Becker, H. Apeler, T. Sirichoke, H. Schroeder, R. Gerzer
and J.-P. Stasch, "Purified soluble guanylyl cyclase expressed in a
baculovirus/Sf9 system: Stimulation by YC-1, nitric oxide, and carbon
oxide", J. Mol. Med. 77 (1999), 14-23. The haem-free guanylate cyclase is
obtained by adding Tween 20 to the sample buffer (0.5% in the final
concentration).

[0740] The activation of sGC by a test substance is reported as x-fold
stimulation of the basal activity. The result for Example 22 is shown in
Table 1:

[0741] It is evident from Table 1 that stimulation both of the
haem-containing and of the haem-free enzyme is achieved. Furthermore,
combination of Example 22 and 2-(N,N-diethylamino)-diazenolate 2-oxide
(DEA/NO), an NO donor, shows no synergistic effect, i.e. the effect of
DEA/NO is not potentiated as would be expected with an sGC activator
acting via a haem-dependent mechanism. In addition, the effect of the sGC
activator according to the invention is not blocked by
1H-1,2,4-oxadiazolo[4,3a]quinoxalin-1-one (ODQ), a haem-dependent
inhibitor of soluble guanylate cyclase, but is in fact increased. The
results in Table 1 thus confirm the mechanism of action of the compounds
according to the invention as activators of soluble guanylate cyclase.

B-2. Action at a Recombinant Guanylate Cyclase Reporter Cell Line

[0742] The cellular action of the compounds according to the invention is
determined at a recombinant guanylate cyclase reporter cell line, as
described in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).

[0743] Representative results for the compounds according to the invention
are listed in Table 2:

[0744] Soluble guanylate cyclase (sGC) converts on stimulation GTP into
cGMP and pyrophosphate (PPi). PPi is detected with the aid of the assay
described below. The signal produced in the assay increases as the
reaction progresses and serves as a measure of the sGC enzyme activity
under the given stimulation.

[0746] The activation of haem-free guanylate cyclase is examined by
addition of 25 μM of 1H-1,2,4-oxa-diazolo[4,3-a]quinoxalin-1-one (ODQ)
to the enzyme solution and subsequent incubation for minutes and compared
to the stimulation of the native enzyme.

[0747] Representative results for the compounds according to the invention
are listed in Table 3:

[0748] Rabbits are anaesthetized and sacrificed by intravenous injection
of thiopental sodium (about 50 mg/kg) and exsanguinated. The saphenous
artery is removed and divided into rings 3 mm wide. The rings are mounted
singly on in each case a pair of triangular hooks open at the end and
made of 0.3 mm-thick special wire (Remanium®). Each ring is placed
under an initial tension in 5 ml organ baths with Krebs-Henseleit
solution which is at 37° C., is gassed with carbogen and has the
following composition: NaCl 119 mM; KCl 4.8 mM; CaCl2×2
H2O 1 mM; MgSO4×7H2O 1.4 mM; KH2PO4 1.2
mM; NaHCO3 25 mM; glucose 10 mM; bovine serum albumin 0.001%. The
force of contraction is detected with Statham UC2 cells, amplified and
digitized via A/D converters (DAS-1802 HC, Keithley Instruments, Munich)
and recorded in parallel on chart recorders. Contractions are induced by
addition of phenylephrine.

[0749] After several (generally 4) control cycles, the substance to be
investigated is added in each further run in increasing dosage, and the
level of the contraction achieved under the influence of the test
substance is compared with the level of the contraction reached in the
last preceding run. The concentration necessary to reduce the contraction
reached in the preceding control by 50% is calculated from this
(IC50). The standard application volume is 5 μl. The proportion
of DMSO in the bath solution corresponds to 0.1%.

[0750] Representative results for the compounds according to the invention
are listed in Table 4:

[0751] A commercially available telemetry system from Data Sciences
International DSI, USA, is employed for the measurements on conscious SH
rats described below.

[0752] The system consists of 3 main components: (1) implantable
transmitters, (2) receivers, which are linked via a multiplexer to a (3)
data acquisition computer. The telemetry system makes it possible to
continuously record the blood pressure and heart rate of conscious
animals in their usual habitat.

[0753] The investigations are carried out on adult female spontaneously
hypertensive rats (SH rats) with a body weight of >200 g. After
transmitter implantation, the experimental animals are housed singly in
type 3 Makrolon cages. They have free access to standard feed and water.
The day/night rhythm in the experimental laboratory is changed by the
room lighting at 6.00 am and at 7.00 pm.

[0754] The telemetry transmitters (TAM PA-C40, DSI) employed are
surgically implanted under aseptic conditions in the experimental animals
at least 14 days before the first experimental use. The animals
instrumented in this way can be employed repeatedly after the wound has
healed and the implant has settled.

[0755] For the implantation, the fasted animals are anaesthetized with
pentobarbital (Nembutal, Sanofi, 50 mg/kg i.p.) and shaved and
disinfected over a large area of their abdomens. After the abdominal
cavity has been opened along the linea alba, the liquid-filled measuring
catheter of the system is inserted into the descending aorta in the
cranial direction above the bifurcation and fixed with tissue glue
(VetBonD®, 3M). The transmitter housing is fixed intraperitoneally to
the abdominal wall muscle, and layered closure of the wound is performed.
An antibiotic (Tardomyocel COMP, Bayer AG, 1 ml/kg s.c.) is administered
postoperatively for prophylaxis of infection.

Outline of Experiment:

[0756] The substances to be investigated are administered orally by gavage
in each case to a group of animals (n=6). The test substances are
dissolved in suitable solvent mixtures, or suspended in 0.5% strength
Tylose, appropriate for an administration volume of 5 ml/kg of body
weight. A solvent-treated group of animals is employed as control.

[0757] The telemetry measuring unit is configured for 24 animals. Each
experiment is recorded under an experiment number.

[0758] Each of the instrumented rats living in the system is assigned a
separate receiving antenna (1010 Receiver, DSI). The implanted
transmitters can be activated externally by means of an incorporated
magnetic switch and are switched to transmission in the run-up to the
experiment. The emitted signals can be detected online by a data
acquisition system (Dataquest® A.R.T. for Windows, DSI) and be
appropriately processed. The data are stored in each case in a file
created for this purpose and bearing the experiment number.

[0760] The acquisition of measured values is repeated under computer
control at 5-minute intervals. The source data obtained as absolute value
are corrected in the diagram with the currently measured barometric
pressure and stored as individual data. Further technical details are
given in the documentation from the manufacturing company (DSI).

[0761] The test substances are administered at 9.00 am on the day of the
experiment. Following the administration, the parameters described above
are measured over 24 hours. After the end of the experiment, the acquired
individual data are sorted using the analysis software (Dataquest®
A.R.T. Analysis). The void value is assumed to be the time 2 hours before
administration of the substance, so that the selected data set includes
the period from 7.00 am on the day of the experiment to 9.00 am on the
following day.

[0762] The data are smoothed over a presettable time by determination of
the average (15-minute average, 30-minute average) and transferred as a
text file to a storage medium. The measured values presorted and
compressed in this way are transferred into Excel templates and
tabulated.

C. Exemplary Embodiments of Pharmaceutical Compositions

[0763] The compounds according to the invention can be converted into
pharmaceutical preparations in the following ways:

[0766] The mixture of compound according to the invention, lactose and
starch is granulated with a 5% strength solution (m/m) of the PVP in
water. The granules are dried and then mixed with the magnesium stearate
for 5 minutes. This mixture is compressed in a conventional tablet press
(see above for format of the tablet). A guideline compressive force for
the compression is 15 kN.

Suspension which can be Administered Orally:

Composition:

[0767] 1000 mg of the compound according to the invention, 1000 mg of
ethanol (96%), 400 mg of Rhodigel® (xanthan gum from FMC,
Pennsylvania, USA) and 99 g of water.

[0768] 10 ml of oral suspension correspond to a single dose of 100 mg of
the compound according to the invention.

Production:

[0769] The Rhodigel is suspended in ethanol, and the compound according to
the invention is added to the suspension. The water is added while
stirring. The mixture is stirred for about 6 h until the swelling of the
Rhodigel is complete.

Solution which can be Administered Orally:

Composition:

[0770] 500 mg of the compound according to the invention, 2.5 g of
polysorbate and 97 g of polyethylene glycol 400.20 g of oral solution
correspond to a single dose of 100 mg of the compound according to the
invention.

Production:

[0771] The compound according to the invention is suspended in the mixture
of polyethylene glycol and polysorbate with stirring. The stirring
process is continued until the compound according to the invention has
completely dissolved.

i.v. Solution:

[0772] The compound according to the invention is dissolved in a
concentration below the saturation solubility in a physiologically
tolerated solvent (e.g. isotonic saline, 5% glucose solution and/or 30%
PEG 400 solution). The solution is sterilized by filtration and used to
fill sterile and pyrogen-free injection containers.